Particulate Comprising a Calcium-Containing Compound and a Sugar Alcohol

ABSTRACT

The present invention relates to a particulate material and a solid dosage form notably tablets comprising a regularly shaped calcium-containing compound such as a calcium salt as a therapeutically and/or prophylactically active substance and a pharmaceutically acceptable sugar alcohol such as, e.g., sorbitol and/or isomalt that has a micro structure as evidenced by SEM. The invention also relates to a process for the preparation of the particulate material and solid dosage form. The process involves agglomeration of the calcium-containing compound and the pharmaceutically acceptable sugar alcohol by means of roller compaction. The particulate material obtained by roller compaction is suitable for use in the further processing of the particulate material into e.g. tablets such as chewing tablets.

FIELD OF THE INVENTION

The present invention relates to a particulate material and a soliddosage form notably tablets comprising a regularly shapedcalcium-containing compound such as a calcium salt as a therapeuticallyand/or prophylactically active substance and a pharmaceuticallyacceptable sugar alcohol such as, e.g., sorbitol and/or isomalt that hasa micro structure as evidenced by SEM. The invention also relates to aprocess for the preparation of the particulate material and solid dosageform. The process involves agglomeration of the calcium-containingcompound and the pharmaceutically acceptable sugar alcohol by means ofroller compaction. The particulate material obtained by rollercompaction is suitable for use in the further processing of theparticulate material into e.g. tablets such as chewing tablets.

The present invention is based on the findings that the result of anagglomeration process by which a calcium-containing compound isagglomerated depends on the particular shape of the calcium-containingcompound and the micro structure of the material used as a binder in theagglomeration process.

BACKGROUND

Calcium is essential for a number of key functions in the body, both asionized calcium and a calcium complex (Campell A K. Clin Sci 1987;72:1-10). Cell behaviour and growth are regulated by calcium. Inassociation with troponin, calcium controls muscle contraction andrelaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).

Calcium selected channels are a universal feature of the cell membraneand the electrical activity of nerve tissue and the discharge ofneurosecretory granules are a function of the balance betweenintracellular and extra cellular calcium levels (Burgoyne R D. BiochimBiophys Acta 1984; 779:201-16). The secretion of hormones and theactivity of key enzymes and proteins are dependent on calcium. Finallycalcium as a calcium phosphate complex confers rigidity and strength onthe skeleton (Boskey A L. Springer, 1988:171-26). Because bone containsover 99% of the total body calcium, skeletal calcium also serves as themajor long-term calcium reservoir.

Calcium salts such as, e.g., calcium carbonate is used as a source ofcalcium especially for patients suffering from or at risk ofosteoporosis. Moreover, calcium carbonate is used as anacid-neutralizing agent in antacid tablets.

Furthermore, calcium may have anticancer actions within the colon.Several preliminary studies have shown high calcium diets or intake ofcalcium supplementation is associated with reduced colon rectal cancer.There is increasing evidence that calcium in combination withacetylsalicylic acid (ASA) and other non-steroidal anti-inflammatorydrugs (NSAIDS) reduce the risk the risk of colorectal cancer.

Recent research studies suggest that calcium might relieve premenstrualsyndrome (PMS). Some researchers believe that disruptions in calciumregulation are an underlying factor in the development of PMS symptoms.In one study, half the women of a 466 person group of pre-menopausalwomen from across the U.S. were tracked for three menstrual cycles andwere given 1200 mg of calcium supplements daily throughout the cycle.The final results showed that 48% of the women who took placebo had PMSrelated symptoms. Only 30% of those receiving calcium tablet did.

Calcium salts like e.g. calcium carbonate is used in tablets and due tothe high dose of calcium required, such tablets are often in the form ofchewable tablets. It is a challenge to formulate chewable tabletscontaining a calcium salt, which tablets have a pleasant taste and anacceptable mouthfeel without the characteristic dominating taste orfeeling of chalk.

Furthermore, i) the high dose of calcium carbonate (normally 300-600 mgof elemental calcium twice daily, corresponding to 750-1500 mg ofcalcium carbonate twice daily), ii) the inherent poor properties ofregular shaped calcium carbonate with respect to tabletting propertieslike compressibility, which accordingly calls for the need of adding oneor more pharmaceutically acceptable excipients in order to obtain asuitable compressibility, and iii) the extremely bad taste or mouthfeelof a calcium salt itself especially with respect to chalkiness make itvery difficult to prepare a tablet that has a suitable small size, whichis conveniently small for a patient. Sufficient taste masking is anothermajor challenge when formulating chewable tablets.

The present inventors have found an easy way for producing e.g. chewabletablets containing a physiologically tolerable calcium-containingcompound by using a granulate comprising agglomerates of thecalcium-containing compound. The granulate is obtained without use ofany solvent (e.g. water), but involves the technique of rollercompaction of the calcium-containing compound to form agglomerateshaving suitable properties for further processing into a solid dosageform such as, e.g., tablets.

EP 0 054 333 (Stauffer Chemical Company) describes a process ofcompacting fine particles of calcium phosphate by means of rollercompacting to obtain a powder. The powder obtained has a larger bulkdensity than the starting material, which makes it suitable for use asan excipient in producing pharmaceutical tablets. In contrast to EP 0054 333 the present invention does not employ roller compaction with theaim of increasing the bulk density of a pharmaceutically acceptableexcipient, but as a novel method for agglomeration, i.e. for building upagglomerates of particles in order to increase the mean particle size toa size that is suitable for further processing of the material into e.g.tablets such as, e.g., chewable tablets that have an acceptable tasteand/or mouthfeel.

Previously it has been described that the quality of thecalcium-containing compound as well as the method for preparation of apharmaceutical composition containing the calcium-containing compoundare of great importance in order to obtain acceptable taste andmouthfeel of a chewable tablet (WO 00/28973). In contrast to WO 00/28973the method according to the invention does not employ a step of bindingthe particles together by a wet granulation process, which means thatthe method according to the invention advantageously can be employedwhen it is desired to incorporate substances that are sensitive towardshumidity. An example of such a substance is vitamin D that often isincluded together with a calcium salt in a pharmaceutically dosage form.The present invention provides a simple and cost-effective alternativemethod to obtain such a dosage form without the need of a step e.g.involving wet granulation.

DESCRIPTION OF THE INVENTION

It has surprisingly been found that roller compaction of acalcium-containing compound together with a pharmaceutically acceptablesugar alcohol that has binding properties improves the properties forpharmaceutical use of the compacts obtained thereby.

As mentioned above, in the present context the process of rollercompacting of a powder is applied as an alternative method to knowngranulation or agglomeration methods, i.e. wet granulation or—whentablets are prepared—direct compression using dry binders. The presentinventors have found that the process of roller compacting is a verymild method that does not destroy the possibility of obtaining productsthat have an acceptable mouthfeel and at the same time are without adominating chalk-like taste or feel. Normally, roller compaction isemployed with the purpose of increasing the bulk density of a particularsubstance or composition e.g. in order to transform a bulky material toa less voluminous material that is easier to use in the manufacturing ofpharmaceutical compositions. To the best of the present inventor'sknowledge, roller compaction has not been employed as a gentlegranulation process that maintains or do not destroy importantproperties of the material (i.e. the calcium-containing compound) sothat an acceptable taste, mouthfeel etc. can be obtained.

With an aim of preparing a smaller tablet that still has acceptabletaste and mouthfeel, the present inventors have found that the usepharmaceutically acceptable sugar alcohols as binding material in theagglomeration process is particularly suitable. However, in order toobtain suitable properties of a roller compacted composition containinga calcium-containing compound, two major factors are important, namelythe properties of the calcium-containing compound itself and the choiceof sugar alcohol used as a binder in the agglomeration process. To thisend the present inventors have found that when a regularly shapedcalcium-containing compound is used, which has very poor compressibilityproperties itself, then—in order to obtain an acceptable end result—itis very important that the sugar alcohol used has a micro structure,i.e. a structure that enables a certain deformation and sufficientdistribution throughout the tablet during the roller compaction processin order to establish sufficient bonding between the individual calcium(and sugar alcohol) particles.

In the present context, the term “regularly shaped” in connection with acalcium-containing compound is intended to denote that the individualparticles as evidenced by SEM have a rounded or smooth-like surface likee.g. the cubic-formed crystals shown in FIG. 15 herein. The regularshape results in a relatively low specific surface area, that is below1.5 m²/g

In the present context, the term “micro structure” used in connectionwith sugar alcohols is intended to denote that a single crystal of thesugar alcohol is a polycrystal such as multiple crystals or fibercrystals comprising smaller units, i.e. the crystals have anidentifiable substructure that is detectable by SEM (e.g. see FIG. 16herein). The micro structure enables a certain deformation andsufficient distribution throughout the tablet during the rollercompaction process in order to establish sufficient bonding between theindividual calcium (and sugar alcohol) particles. Furthermore, asufficient compressibility is required, cf. the examples herein.

Moreover, in contrast to what is general knowledge within the field ofpharmaceutical formulation, the present inventors have found that asugar alcohol like sorbitol is not suitable for use in the standardquality generally recommended. This quality has a mean particle size ofabout 300 μm, but as demonstrated in the examples herein such a meanparticle size is too large in order to enable a sufficient distributionof sorbitol particles around the particles of the calcium-containingcompound resulting in tablets having unacceptable properties withrespect to crushing strength. The particle size of e.g. sorbitol must bemuch smaller in order to obtain good and acceptable results with respectto crushing strength.

Accordingly, the pharmaceutically acceptable sugar alcohol employedaccording to the invention has a mean particle size of at the most about150 μm such as, e.g., at the most about 110 μm, at the most about 100μm, at the most about 90 μm, at the most about 80 μm, at the most about70 μm, at the most about 60 μm, at the most about 50 μm, at the mostabout 40 μm, at the most about 30 μm, at the most about 20 μm or about10 μm.

In specific embodiments, the pharmaceutically acceptable sugar alcoholemployed has a mean particle size in a range of from about 5 to about150 μm such as, e.g., from about 5 to about 110 μm or from about 5 toabout 80 μm.

Furthermore, it would have been expected that use of e.g. sorbitol in amuch smaller particle size would lead to stability problems as it isknown that sorbitol is hygroscopic and a smaller particle size increasesthe surface area and thereby the risk of adsorbing moisture e.g. fromthe surroundings. However, as demonstrated herein, tablets preparedusing a granulate obtained by roller compaction of a compositioncontaining the calcium-containing compound and e.g. sorbitol having amean particle size well below 300 μm are stable with respect to crushingstrength, i.e. the crushing strength of the tablets when stored in openpetri dishes at 25° C. and 60% RH changes at the most 50% such as, e.g.at the most about 40%, at the most about 30%, at the most about 20%, atthe most about 15%, at the most about 10% during a time period thatstarts 5 days after manufacture and runs during the remaining storageperiod e.g. 1 month, 3 months etc. The crushing strengths of tablets ofthe invention should be in a range of from about 70 to about 140 N.

Such improved stability indicates that products obtained as describedherein are suitable for so-called zone 3 or 4 countries (as defined inICH Q1F), i.e. countries that have a relatively high average temperatureand relative humidity.

In one aspect, the invention relates to a process for the preparation ofa particulate material or a solid dosage form comprising one or moreregularly shaped calcium-containing compound as an active substance andone or more pharmaceutically acceptable sugar alcohols having a microstructure, the process involving roller compaction of a compositioncontaining the calcium-containing compound and the sugar alcohol. Theinvention also relates to the particulate material as such as well as toa solid dosage form based on the particulate material. The sugaralcohols employed have binding properties and—as in the case of sorbitoland isomalt—preferably sweetening properties.

In order to achieve satisfactory results, the sugar alcohol (binder)must be present in the particulate material in a concentration of atleast about 5% w/w such as, e.g., at least about 10% w/w, at least about15% w/w or at least about 20% w/w.

Use of roller compaction as a means for agglomeration of acalcium-containing compounds to obtain a particulate material that issuitable for use in the preparation of e.g. chewable tablets having anacceptable taste and mouthfeel, has two critical parameters, namely theshape of the calcium carbonate crystals and the structure of the sugaralcohol crystal. Moreover, the pharmaceutically acceptable sugar alcohol(binder) is normally present in a minimum concentration of about 5% w/wor about 10% w/w.

Furthermore, it has been also been observed that when acalcium-containing compound is employed that has a bulk density of atleast about 0.7 g/ml (such as e.g. calcium carbonate in the form ofScoralite) then the bulk density of the composition (containing thecalcium-containing compound and the sugar alcohol) subjected to rollercompaction is not remarkably higher than the bulk density of thecalcium-containing compound itself (i.e. before roller compaction).Thus, when such a calcium carbonate quality is used, the bulk densitybefore and after roller compaction may not change much, i.e. the changein bulk density between the particulate material obtained and thecalcium-containing compound used is at the most about 40% such as, e.g.,at the most about 30% or at the most about 20% calculated as[(d_(particulate material)−d_(calcium-containing compound))/d_(particulate material)]×100%.

As mentioned above, the present invention relates to a particulatematerial comprising one or more regularly shaped calcium-containingcompounds as an active substance and one or more pharmaceuticallyacceptable sugar alcohols having a micro structure. Normally, such aparticulate material is further processed into a convenient dosage formsuch as tablets and such tablets must have suitable technical propertiesin order to withstand normal handling etc. Furthermore, when chewabletablets are prepared, the tablets must not be so hard, i.e. have anunacceptable high crushing strength, so that it becomes difficult for apatient to chew. Accordingly, it is important to balance the crushingstrength to an acceptable level. As shown in the example herein, it ispossible to determine whether a specific sugar alcohol is suitable foruse in the preparation of a particulate material according to theinvention by subjecting the sugar alcohol to two tests, namely i) a SEMphoto showing that the sugar alcohol has a micro structure and ii) atest showing the compressibility properties of the sugar alcohol itself.To this end, the pharmaceutically acceptable sugar alcohol—whencompressed into tablets containing 100% w/w of the sugar alcohol using11.29 mm flat faced punches and a max compression force of 25 kN—has aslope of correlation between crushing strength (measured in N) andcompression pressure (measured in (N) of 7×10⁻³ or more, when testedusing a Schleuniger Hardness Autotester 4 or Schleuniger Tablet tester6D and a tablet placed with the longest dimension orthogonal to the jawsof the crushing strength apparatus.

The inventors have found that it is of great advantage in the rollercompaction process to use a pharmaceutically acceptable sugar alcoholthat has binding and sweetening properties. Examples of suitable bindersor sweeteners include sorbitol, maltitol, xylitol, fructose, lactitol,isomalt, tagatose and manitol. Sorbitol has a sweetening effect(compared to sucrose) of 0.55; maltitol that has a sweetening effect of<1; xylitol that has a sweetening effect of 1, isomalt that has asweetening effect of <0.5, etc.

In order to ensure a sufficient distribution of the pharmaceuticallyacceptable sugar alcohol between the individual particles of thecalcium-containing compound during the roller compaction, the inventorshave found that the binder suitably have a mean particle size of at themost about 110 μm such as, e.g., at the most about 100 μm, at the mostabout 90 μm, at the most about 80 μm, at the most about 70 μm, at themost about 60 μm, at the most about 50 μm, at the most about 40 μm, atthe most about 30 μm, at the most about 20 μm or about 10 μm. Examplesof such materials are sorbitol and isomalt.

In the literature (see Pharmaceutical Technology, volume 1 (tablettingtechnology), Michael H. Rubinstein (ed.), Ellis Horwood Ltd, 1987) ithas been stated that sorbitol has good tabletting properties and thatthe admixing of this excipient will increase the tablet strength.However, it has also been stated that in order to get this effect thesorbitol should be of the “instant” quality that is manufactured byspray-drying. The optimal particle size of sorbitol “instant” has beendescribed as having 60-90% between 212-500 μm when determined by sieveanalysis. The recommended concentration in the tablet is 30-80%.However, in the context of the present invention, sorbitol can be usedas a binder (having sweetening properties) in tablets based on rollercompaction and important deviations from the reported use of sorbitolare necessary:

1. Sorbitol should be finely dispersed or distributed between theparticles of the calcium-containing compound in order to secure anoptimal or a good as possible binding; this leads to limitations withrespect to the particle size of sorbitol.

2. A particle size of sorbitol corresponding to D_(0.5)<100 μm seems tobe suitable. The particle size is measured employing Malvern Mastersizerand the size is given as D(v; 0.5).

3. The concentration of sorbitol should exceed that of 5% w/w and approx20% w/w seems to be fine.

4. Sorbitol of the “instant” quality mentioned above would failcompletely if the above described and relatively large particle sizedistribution was used.

Especially two sugar alcohols have proved to be suitable for use in theroller compaction process, namely sorbitol and isomalt. However, it iscontemplated that other sugar alcohols also may be available in aquality that fulfils the above-mentioned criteria, and such sugaralcohols are envisaged to be suitable for use according to theinvention. Below is mentioned other sugar alcohols, that may fulfil theabove-mentioned criteria.

In a specific embodiment, the sugar alcohol is sorbitol, notable asorbitol that has a mean particle size in a range of from about 25 toabout 50 μm such as, e.g., from about 35 to about 45 μm or from about 30to about 45 μm.

In another embodiment, the sugar alcohol is isomalt, notably an isomaltthat has a mean particle size in a range of from about 20 to about 50 μmsuch as, e.g., from about 25 to about 35 μm or from about 20 to about 35μm.

Provided that a sugar alcohol is employed that fulfils theabove-mentioned criteria it is possible to use one or more sugaralcohols that not necessarily fulfils these criteria, but has otherfunctions e.g. as a sweetener. Such sugar alcohols are typicallyselected from the group consisting of mannitol, xylitol, maltitol,inositol, and lactitol, and mixtures thereof. Examples are Sorbitols,Neosorb P100T, Sorbidex P1666B0 and Sorbogem Fines Crystalline Sorbitolavailable from Roquette Freres, Cerestar and SPI Polyols Inc.respectively. Maltisorb P90 (maltitol) available from Roquette Freres,Xylitol CM50, Fructofin CM (fructose) and Lactitol CM50 available fromDanisco Sweeteners, Isomalt ST-PF, Isomalt DC100, Gaio Tagatose andManitol available from Palatinit, Arla Foods and Roquette, Freresrespectively. Further examples of suitable saccharide-basedbinders/sweeteners include sucrose, dextrose. Specific qualities ofsorbitol and isomalt that do not fulfil the above-mentioned criteria mayof course also be added.

In a specific embodiment, a particulate material according to theinvention may comprise a mixture of sorbitol and xylitol. In such cases,the weight ratio between sorbitol and xylitol is normally in a range offrom about 1:0.1 to about 1:1.5 such as, e.g., about 1:1. A mixture ofisomalt and xylitol is also suitable and in such cases, the weight ratiobetween isomalt and xylitol is normally in a range of from about 1:0.1to about 1:1.5 such as, e.g., about 1:1.

In a paragraph given in the following, a description ofcalcium-containing compounds is given. However, as mentioned hereinbefore, the calcium-containing compound for use in the roller compactionprocess according to the invention has a regular shape such as a calciumsalt like calcium carbonate in specific qualities. In preferred aspect,the calcium salt is calcium carbonate and notably with a shape and amean particle size corresponding to that of Scoralite 1B or Merck 2064.In a specific embodiment, the calcium carbonate is Scoralite 1B or Merck2064.

However, the above-mentioned calcium carbonate may be used in admixturewith other calcium-containing compounds such as, e.g., those mentionedherein in the following paragraph, especially calcium citrate, calciumlactate, calcium phosphate including tricalcium phosphate, calciumgluconate, bisglycino calcium, calcium citrate maleate, hydroxyapatiteincluding solvates, and mixtures thereof.

Normally, the content of the regularly shaped calcium-containingcompound in the particulate material is in a range of from about 40% toabout 100% w/w such as, e.g., from about 45% to about 98% w/w, fromabout 50% to about 95% w/w, from about 55% to about 90% w/w or at leastabout 60% w/w, at least about 65% w/w, at least about 70% w/w or atleast about 75% w/w.

The particulate material obtained by roller compaction may comprise 100%w/w of the calcium-containing compound or it may comprise from about 50%to about 90% w/w such as, e.g., from about 70 to about 80% w/w of thetotal amount of calcium-containing compound contained in the tablet.Accordingly, a part of the total amount of calcium-containing compoundmay be added after roller compaction.

As mentioned above, during the roller compaction process, the calciumcarbonate and the sugar alcohol are brought in close contact and due tothe micro structure of the crystal of the sugar alcohol, the sugaralcohol crystals are squeezed between the calcium carbonate crystal.Accordingly, a SEM photo of the particulate material—when compressedinto a tablet—shows that a surface of a deformed particle of thepharmaceutically acceptable sugar alcohol is in close contact withsurfaces of the crystals of the one or more calcium-containing compound.

A particulate material according to the invention may further compriseone or more pharmaceutically acceptable excipients or additives, or oneor more therapeutically, prophylactically and/or diagnostically activesubstances. A description of pharmaceutically acceptable excipientssuitable for use in the present context is given herein.

A particular active substance of interest is a vitamin D.

Furthermore, roller compaction of a composition containing acalcium-containing compound and a sugar alcohol to obtain a particulatematerial according to the invention leads to a particulate material thathas such a flowability that—when tablets are prepared from theparticulate material optionally admixed with at the most 10% w/w suchas, e.g. at the most about 7.5% w/w or at the most about 5% w/w of aglidant using a tabletting machine operating at least 300 tablets permin—the mass variation of the tablets obtained fulfils the requirementsgiven in Ph. Eur. The tabletting machine may be operating at e.g. 1000tablets/min or even higher such as, e.g., 2000 tablets/min, 3000tablets/min, 4000 tablets/min, 5000 tablets/min, 6500 tablets/min etc.The dwell time during the preparation of the tablets is at the mostabout 1 sec.

In a specific embodiment a particulate material according to theinvention contains from about 60 to about 95% w/w of thecalcium-containing compound and from about 5 to about 40% w/w of thepharmaceutically acceptable sugar alcohol, provided that the sum doesnot exceed 100% w/w.

In another specific embodiment a particulate material according to theinvention contains from about 60 to about 94% w/w such as, e.g., fromabout 65% to about 80% w/w of the calcium-containing compound, fromabout 5 to about 35% w/w such as, e.g., from about 15 to about 30% w/wof the pharmaceutically acceptable sugar alcohol and from about 1 toabout 15% w/w of one or more pharmaceutically acceptable excipientsand/or active substances, provided that the sum of ingredients amountsto 100% w/w.

More specifically, a particulate material according to the inventionpreferably contains from about 65% to about 80% w/w such as, e.g., fromabout 70% to about 75% w/w of the calcium-containing compound and fromabout 15% to about 25% w/w such as, e.g., from about 20 to about 25% w/wof sorbitol or isomalt or mixtures thereof.

A particulate material according to the invention may be used as such,but normally it is manufactured into a suitable solid dosage form. Oneor more pharmaceutically acceptable excipients may be added in order toprepare the dosage form. The dosage form is intended for oraladministration e.g. in the form of a single unit or a multiple unitdosage form such as, e.g., in the form of tablets, capsules, sachets,beads, pellets or the like.

In a preferred embodiment, the solid dosage form according to theinvention is in the form of tablets.

In a specific embodiment the tablets have a shape and dimensionsessentially as shown in FIG. 24 herein. This shape is especiallydesigned to easily break the tablet into two halves of essentially thesame size, i.e. essentially containing the same amount of calcium. Thebreakage is provided by placing the tablet on a flat surface e.g. atable and then by use of e.g. two fingers pressing simultaneously oneach end of the tablet. Due to the fact that the tablet is in contactwith the table only in one point this is possible.

A solid dosage form according to the invention may contain an amount ofthe one or more calcium-containing compounds corresponding to from about300 to about 1200 mg calcium such as, e.g., from about 400 to about 600mg calcium. Normally, the total concentration of the one or morecalcium-containing compound in the dosage form is in a range of fromabout 40% to about 99% w/w such as, e.g., from about 45% to about 98%w/w, from about 50% to about 95% w/w, from about 55% to about 90% w/w orat least about 60% w/w, at least about 65% w/w, at least about 70% w/w.

In a specific embodiment, the total concentration of the particulatematerial contained in the dosage form is from about 65% to about 100%w/w such as, e.g., from about 70% to about 98% w/w, from about 75% toabout 95% w/w, from about 80% to about 95% or from about 85% to about95% w/w.

In another specific embodiment, a solid dosage form according to theinvention contains from about 60% to about 95% w/w of thecalcium-containing compound and from about 5% to about 40% w/w of thepharmaceutically acceptable sugar alcohol, provided that the sum doesnot exceed 100% w/w. Alternatively, a solid dosage form contains fromabout 60 to about 94% w/w such as, e.g., from about 65% to about 80% w/wof the calcium-containing compound, from about 5 to about 35% w/w suchas, e.g., from about 15 to about 30% w/w of the pharmaceuticallyacceptable sugar alcohol and from about 1 to about 15% w/w of one ormore pharmaceutically acceptable excipients and/or active substances,provided that the sum of ingredients amounts to 100% w/w.

A SEM photo of a fractured surface of the solid dosage form shows that asurface of a deformed particle of sugar alcohol is in close contact withsurfaces of the one or more calcium-containing compound.

As mentioned herein before, a solid dosage form according to theinvention is stable. Accordingly, the crushing strength of the tabletswhen stored in open petri dishes at 25° C. and 60% RH at the mostchanges 50% such as, e.g. at the most about 40%, at the most about 30%,at the most about 20%, at the most about 15%, at the most about 10%during a time period that starts 5 days after manufacture and runsduring the remaining storage period. Acceptable stability is obtained ifa tablet during the whole storage period (e.g. 1 month, 3 months) inopen Petri dishes has a crushing strength in a range of from about 70 toabout 140 N.

In a preferred aspect, a solid dosage form is in the form of a chewable,suckable and/or swallowable tablet. Importantly for chewable tablets isthe taste and such tablets of the invention must have an acceptabletaste with respect to sweetness, flavour and chalkiness when tested by aprofessional/skilled sensory test panel of at least 6 persons.

A solid dosage form according to the invention may comprise a sweetenerselected from the group consisting of dextrose, fructose, glycerin,glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol,sorbitol, sucrose, tagatose, trehalose, xylitol, alitame, aspartame,acesulfam potassium, cyclamic acid, cyclamate salt (e.g. calciumcyclamate, sodium cyclamate), neohesperidine dihydrochalcone, thaumatin,saccharin, saccharin salt (e.g. ammonium saccharin, calcium saccharin,potassium saccharin, sodium saccharin), and mixtures thereof.

The invention also relates to a process for the preparation of aparticulate material as defined above, the process comprises rollercompaction of a composition comprising the regularly shapedcalcium-containing compound and one or more pharmaceutically acceptablesugar alcohols having a micro structure. Details concerning this aspectappear from the appended claims and from the description above relatingto the particulate material apply mutatis mutandis to this and otheraspects of the invention.

A further aspect of the invention is to combine the manufacture of aparticulate material and the manufacture of tablets. By use of pocketrollers on the roller compactor a powder mixture can be transformeddirectly into a solid dosage form, that is a tablet.

A further aspect of the invention is a process for preparing a tabletcomprising a calcium-containing compound, the process comprises

i) preparing a particulate material as defined herein,ii) optionally admixing one or more pharmaceutically acceptableexcipients or additive and/or one or more active substances, andiii) compressing the material into tablets.

Normally, the compression in step iii) is performed at a compressionforce that is adjusted with respect to the diameter and the desiredheight of the tablet so that the compression force applied is at themost about 80 kN such as, e.g., at the most 70 kN, at the most 60 kN, atthe most 50 kN, at the most about 40 kN, at the most about 30 kN or atthe most about 20 kN when tablets having a diameter of about 16 mm or iscapsule shaped (9.4×18.9 mm) and a resulting height of at the most about10 mm such as, e.g., about 9 mm, about 8 mm or about 7 mm or about 6 mmare obtained.

Specifically, the invention relates to a process according for thepreparation of a tablet comprising

i) calcium carbonateii) sorbitol and/or isomalt,iii) a vitamin D, andiv) optionally one or more pharmaceutically acceptable excipients.

The tablet may comprise

i) from about 50% to about 90% w/w of calcium carbonate,ii) from about 5 to about 30% w/w of sorbitol and/or isomalt,iii) from about 0.01 to about 1% w/w of a vitamin D, andiv) optionally one or more pharmaceutically acceptable excipientswith the proviso that the total amount of ingredients corresponds toabout 100% w/w.

Calcium-Containing Compound

The calcium-containing compound contained in a particulate material madeaccording to the invention is a physiologically tolerablecalcium-containing compound that is therapeutically and/orprophylactically active.

Calcium is essential for a number of key functions in the body, both asionized calcium and a calcium complex (Campell A K. Clin Sci 1987;72:1-10). Cell behaviour and growth are regulated by calcium. Inassociation with troponin, calcium controls muscle contraction andrelaxation (Ebashi S. Proc R Soc Lond 1980; 207:259-86).

Calcium selected channels are a universal feature of the cell membraneand the electrical activity of nerve tissue and the discharge ofneurosecretory granules are a function of the balance betweenintracellular and extra cellular calcium levels (Burgoyne R D. BiochimBiophys Acta 1984; 779:201-16). The secretion of hormones and theactivity of key enzymes and proteins are dependent on calcium. Finallycalcium as a calcium phosphate complex confers rigidity and strength onthe skeleton (Boskey A L. Springer, 1988:171-26). Because bone containsover 99% of the total body calcium, skeletal calcium also serves as themajor long-term calcium reservoir.

Calcium salts such as, e.g., calcium carbonate is used as a source ofcalcium especially for patients suffering from or at risk ofosteoporosis. Moreover, calcium carbonate is used as anacid-neutralizing agent in antacid tablets.

As mentioned above, calcium has a number of important functions withinthe mammalian body in particular in humans. Furthermore, in many animalmodels, chronic low calcium intake produces osteopenia. The osteopeniaaffects cancellous bone more than cortical bone and may not becompletely reversible with calcium supplementation. If the animal isgrowing reduced calcium intake leads to stunting. In the premature humanneonate the higher the calcium intake, the greater the increase inskeletal calcium accretion which, if high enough, can equal gestationalcalcium retention. During growth chronic calcium deficiency causesrickets. Calcium supplements in both pre- and postpubertal healthychildren leads to increased bone mass. In adolescents the higher thecalcium intake, the greater the calcium retention, with the highestretention occurring just after menarche. Taken together, these datasuggest that in children and adolescents considered to be taking anadequate intake of calcium, peak bone mass can be optimized bysupplementing the diet with calcium. The mechanisms involved inoptimizing deposition of calcium in the skeleton during growth areunknown. They are probably innate properties of the mineralizationprocess that ensures optimal calcification of the osteoid if calciumsupplies are high. The factors responsible for stunting of growth instates of calcium deficiency are also unknown but clearly involve growthfactors regulating skeletal size.

In adults calcium supplementation reduces the rate of age-related boneloss (Dawson-Hughes B. Am J Clin Nut 1991; 54:S274-80). Calciumsupplements are important for individuals who cannot or will nor achieveoptimal calcium intakes from food. Furthermore, calcium supplement isimportant in the prevention and treatment of osteoporosis etc.

Furthermore, calcium may have anticancer actions within the colon.Several preliminary studies have shown high calcium diets or intake ofcalcium supplementation is associated with reduced colon rectal cancer.There is increasing evidence that calcium in combination withacetylsalicylic acid (ASA) and other non-steroidal anti-inflammatorydrugs (NSAIDS) reduce the risk the risk of colorectal cancer.

Recent research studies suggest that calcium might relieve premenstrualsyndrome (PMS). Some researchers believe that disruptions in calciumregulation are an underlying factor in the development of PMS symptoms.In one study, half the women of a 466 person group of pre-menopausalwomen from across the U.S. were tracked for three menstrual cycles andwere given 1200 mg of calcium supplements daily throughout the cycle.The final results showed that 48% of the women who took placebo had PMSrelated symptoms. Only 30% of those receiving calcium tablets did.

Calcium salts like e.g. calcium carbonate is used in tablets and due tothe high dose of calcium required, such tablets are often in the form ofchewable tablets. It is a challenge to formulate e.g. chewable tabletscontaining a calcium salt, which tablets have a pleasant taste and anacceptable mouth feel without the characteristic dominating taste orfeeling of chalk.

A calcium-containing compound for use according to the invention may bee.g. bisglycino calcium, calcium acetate, calcium carbonate, calciumchloride, calcium citrate, calcium citrate malate, calcium cornate,calcium fluoride, calcium glubionate, calcium gluconate, calciumglycerophosphate, calcium hydrogen phosphate, calcium hydroxyapatite,calcium lactate, calcium lactobionate, calcium lactogluconate, calciumphosphate, calcium pidolate, calcium stearate and tricalcium phosphate.Other calcium sources may be water-soluble calcium salts, or complexeslike e.g. calcium alginate, calcium-EDTA and the like or organiccompounds containing calcium like e.g. calcium organophosphates. Use ofbone meal, dolomite and other unrefined calcium sources is discouragedbecause these sources may contain lead and other toxic contaminants.However, such sources may be relevant if they are purified to a desireddegree.

The calcium-containing compound may be used alone or in combination withother calcium-containing compounds.

Of specific interest is bisglycino calcium, calcium acetate, calciumcarbonate, calcium chloride, calcium citrate, calcium citrate malate,calcium cornate, calcium fluoride, calcium glubionate, calciumgluconate, calcium glycerophosphate, calcium hydrogen phosphate, calciumhydroxyapatite, calcium lactate, calcium lactobionate, calciumlactogluconate, calcium phosphate, calcium pidolate, calcium stearateand tricalcium phosphate. Mixtures of different calcium-containingcompounds may also be used. As appears from the examples herein, calciumcarbonate is especially suitable for use as a calcium-containingcompound and calcium carbonate has a high content of calcium.

Of particular interest is calcium carbonate.

Normally, a tablet made according to the invention contains an amount ofthe calcium-containing compound corresponding to from about 100 to about1000 mg Ca such as, e.g., from about 150 to about 800 mg, from about 200to about 700 mg, from about 200 to about 600 mg or from about 200 toabout 500 mg Ca.

Calcium Carbonate

Calcium carbonate can be in three different crystal structures: calcite,aragonite and vaterite. Mineralogically, these are specific mineralphases, which relate to the distinct arrangement of the calcium, carbonand oxygen atoms in the crystal structure. These distinct phasesinfluence the shape and symmetry of the crystal forms. For example,calcite is available in four different shapes: scalenohedral, prismatic,spherical and rhombohedral, and aragonit crystals can be obtained ase.g. discrete or clustered needle-like shapes. Other shapes are alsoavailable such as, e.g., cubic shapes (Scoralite 1A+B from Scora).

As shown in the examples herein, a particular suitable quality ofcalcium carbonate is calcium carbonate having a mean particle size of 60μm or less such as, e.g., 50 μm or less or 40 μm or less.

Furthermore, an interesting quality of calcium carbonate has a bulkdensity below 2 g/mL.

Calcium carbonate 2064 Merck (available from Merck, Darmstadt, Germany)that has a mean particle size of 10-30 μm, an apparent bulk density of0.4 to 0.7 g/mL, and a specific surface area of 0.3 m²/g;

Calcium carbonate 2069 Merck (available from Merck, Darmstadt, Germany)that has a mean particle size of approx. 3.9 μm, and an apparent bulkdensity of 0.4 to 0.7 g/mL;

Scoralite 1A (available from Scora Watrigant SA, France) has a meanparticle size of 5 to 20 μm, an apparent bulk density of 0.7 to 1.0g/mL, and a specific surface area of 0.6 m²/g;

Scoralite 1B (available from Scora Watrigant SA, France) has a meanparticle size of 10-25 μm, an apparent bulk density of 0.9 to 1.2 g/mL,and a specific surface area of 0.4 to 0.6 m²/g;

Scoralite 1A+B (available from Scora Watrigant SA, France) have a meanparticle size of 7-25 μm, an apparent bulk density of 0.7 to 1.2 g/mL,and a specific surface area of 0.35 to 0.8 m²/g;

Pharmacarb LL (available from Chr. Hansen, Mahawah N.J.) L has a meanparticle size of 12-16 μm, an apparent bulk density of 1.0 to 1.5 g/mL,and a specific surface area of 0.7 m²/g;

Sturcal H has a mean particle size of approx. 4 μm, an apparent bulkdensity of 0.48 to 0.61 g/mL;

Sturcal F has a mean particle size of approx. 2.5 μm, an apparent bulkdensity of 0.32 to 0.43 g/mL;

Sturcal M has a mean particle size of 7 μm, an apparent bulk density of0.7 to 1.0 g/mL, and a specific surface area of 1.0 m²/g;

Mikhart 10, SPL, 15, 40 and 65 (available from Provencale, Provencale,France);

Mikhart 10 has a mean particle size of 10 μm,

Mikhart SPL has a mean particle size of 20 μm,

Mikhart 15 has a mean particle size of 17 μm,

Mikhart 40 has a mean particle size of 30 μm, an apparent bulk densityof 1.1 to 1.5 g/mL;

Mikhart 65 has a mean particle size of 60 μm, an apparent bulk densityof 1.25 to 1.7 g/mL;

Omyapure 35, (available from Omya S.A.S, Paris, France) has a meanparticle size of 5-30 μm, and a specific surface area of 2.9 m²/g;

Socal P2PHV (available from Solvay, Brussels, Belgium) has a meanparticle size of 1.5 μm, an apparent bulk density of 0.28 g/mL, and aspecific surface area of 7.0 m²/g;

Calci Pure 250 Heavy, Calci Pure 250 Extra Heavy and Calci Pure GCC HD212 with a mean particle size of 10-30 μm, an apparent bulk density of0.9-1.2 g/ml, and a specific surface area of 0.7 m²/g (available fromParticle Dynamic Inc., St. Louis Mont.).

The content of the calcium-containing compound in a tablet madeaccording to the present invention is in a range from about 40% to about100% w/w such as, e.g., from about 45% to about 98% w/w, from about 50%to about 95% w/w, from about 55% to about 90% w/w or at least about 60%w/w, at least about 65% w/w, at least about 70% w/w or at least about75% w/w.

Normally, the dose of calcium for therapeutic or prophylactic purposesis from about 350 mg (e.g. newborn) to about 1200 mg (lactating women)daily. The amount of the calcium-containing compound in the tablets canbe adjusted to that the tablets are suitable for administration 1-4times daily, preferably once or twice daily.

As mentioned above, the granulate obtained by the method according tothe invention may be used as such, but it is also very suitable forfurther manufacturing into solid dosage forms like e.g. tablets,capsules or sachets.

A person skilled in the art will know how to adjust the composition andthe various process parameters in order to obtain a desiredcalcium-containing product.

In one embodiment of the invention, the granulate obtained by thepresent method is intended to be manufactured into tablets. Often it isnecessary to add one or more pharmaceutically acceptable excipients(e.g. lubricants) in order to avoid adherence and/or increaseflowability of the granulate obtained. Accordingly, the method may alsocomprise a step of mixing the granulate obtained with one or morepharmaceutically acceptable excipients.

In the event that it is desired to include other active substances thanthe calcium-containing compound, the method may also comprise a step ofadding one or more therapeutically, prophylactically and/ordiagnostically active substance to the granulate obtained.

Such substances include one or more nutrients such as, e.g., one or morevitamins or minerals. In a specific embodiment, the further activesubstance is a D-vitamin such as, e.g., D₃ vitamin, D₂ vitamin orderivatives thereof.

D Vitamin or Other Active Substances

A particulate material as well as a tablet obtained according to theinvention may comprise a further therapeutically and/or prophylacticallyactive substance. Of particular interest are one or more D-vitamincompounds. Non-limitating examples are dry vitamin D3, 100 CWS availablefrom Roche and dry vitamin D3 100 GFP available from BASF.

A particulate material or tablet made according to the invention maycomprise a further therapeutically and/or prophylactically activesubstance, or it may contain one or more nutrients such as, e.g. one ormore vitamins or minerals. Of specific interest are e.g. vitamin B,vitamin C, vitamin D and/or vitamin K and minerals like e.g. zinc,magnesium, selenium etc.

Of particular interest are one or more D-vitamin compounds such as,e.g., Vitamin D₂ (ergocalciferol) and Vitamin D₃ (cholecalciferol)including dry vitamin D₃, 100 CWS available from Roche and dry vitaminD₃100 GFP available from BASF.

In addition to its action on calcium and skeletal homeostasis, vitamin Dis involved in the regulation of several major systems in the body. Theactions of vitamin D are medicated at the genome by a complex formed by1,25-(OH)₂ vitamin D mainly produced in the kidney, with the vitamin Dreceptor (VDR). The latter is widely distributed in many cell types. The1,25-(OH)₂ vitamin D/VDR complex has important regulatory roles in celldifferentiation and in the immune system. Some of these actions areprobably dependant on the ability of certain tissues other than thekidney to produce 1,25-(OH)₂ vitamin D locally and act as a paracrine(Adams J S et al. Endocrinology 1996; 137:4514-7).

In humans, deficiency of vitamin D results in rickets in children andosteomalacia in adults. The basic abnormality is a delay in the rate ofmineralization off osteoid as it is laid down by the osteoblast (PeacockM. London Livingstone, 1993:83-118). It is not clear whether this delayis due to a failure of a 1,25-(OH)₂ vitamin D-dependant mechanism in theosteoblast or to reduced supplies of calcium and phosphate secondary tomalabsorption or a combination of both. Accompanying the mineralizationdelay, there is reduced supply of calcium and phosphate, severesecondary hyperparathyroidism with hypocalcaemia and hypophosphatemiaand increased bone turnover.

Vitamin D insufficiency, the preclinical phase of vitamin D deficiency,also causes a reduced calcium supply and secondary hyperparathyroidism,albeit of a milder degree than found with deficiency. If this stateremains chronic, osteopenia results. The biochemical process underlyingthis state of calcium insufficiency is probably inappropriate level of1,25-(OH)₂ vitamin D due to a reduction in its substrate 25-OHD (FrancisR M et al. Eur J Clin Invest 1983; 13:391-6). The state of vitamin Dinsufficiency is most commonly found in the elderly. With age there is adecrease in serum 25-OH vitamin D due to decreased sunlight exposure andpossible to decreased skin synthesis. Furthermore, in the elderly thecondition is exacerbated by a decrease in calcium intake and aparadoxical decrease in calcium absorption. The reduction in renalfunction with age giving rise to reduced renal 1,25-(OH)₂ vitamin Dproduction may be a contributing factor. There are a number of studiesof the effects of vitamin D supplementation on bone loss in the elderly.Some are without calcium supplementation and others are with calciumsupplementation. It appears from the studies that although vitamin Dsupplementation is necessary to reverse deficiency and insufficiency, itis even more important as far as the skeleton is concerned to providecalcium supplementation since the major skeletal defect is calciumdeficiency. In literature based on clinical trials, recent findingssuggest trends of need for higher doses of vitamin D for the elderlypatients (Compston J E. BMJ 1998; 317:1466-67). An open quasi-randomisedstudy of annual injections of 150.000-300.000 IU of vitamin D(corresponding to approx. 400-800 IU/day) showed a significant reductionin overall fracture rate but not in the rate of hip fracture in treatedpatients (Heikinheimo R J et al. Calcif Tissue Int 1992; 51:105-110).

As it appears from above, a combination of calcium and vitamin D is ofinterest. The recommended Daily Allowance (RDA) of calcium and vitaminD₃ are as follows (European Commission. Report on osteoporosis in theEuropean Community. Action for prevention. Office for officialPublications of the European Communities, Luxembourg 1998):

Group Age (years) Calcium (mg)* Vitamin D₃ (μg) Newborn   0-0.5 40010-25  0.5-1.0 360-400 10-25  Children 1.0-3.0 400-600 10 4.0-7.0450-600 0-10 8.0-10  550-700 0-10 Men 11-17  900-1000 0-10 18-24 900-1000 0-15 25-65 700-800 0-10 65+ 700-800 10 Women 11-17 900-10000-15 18-24  900-1000 0-10 25-50 700-800 0-10 51-65 800 0-10 65+ 700-80010 Pregnant 700-900 10 Lactating 1200  10 *RDA of calcium varies fromcountry to country and is being re-evaluated in many countries.

Vitamin D is very sensitive towards humidity and is subject todegradation. Therefore, vitamin D is often administered in a protectivematrix. Accordingly, when tablets are prepared containing a vitamin D itis of utmost importance that the compression forces applied during thetabletting step do not decrease the protective effect of the matrix andthereby impair the stability of vitamin D. To this end, the combinationof the various ingredients in a granulate or tablet made according tothe invention has proved to be very suitable in those cases wherevitamin D also is incorporated into the composition as it is possible toemploy a relatively low compression force during tabletting and stillachieve a tablet with suitable mechanical strength (crushing strength,friability etc.).

As indicated above, a tablet containing vitamin D is contemplated tofulfil the following requirements with respect to stability:

After storage in a closed container at 25° C. at 60% relative humidity(RH) for at least 6 month such as, e.g., at least 1 year, at least 1.5years, at least 2 years or at least 5 years, there is a decrease in thecontent of D vitamin of at the most about 15% w/w such as, e.g., at themost about 10% w/w or at the most about 5% w/w.

After storage in a closed container at 40° C. at 75% relative humidity(RH) for at least 1 month such as, e.g., at least 2 months, at least 4months or at least 6 months, there is a decrease in the content of Dvitamin of at the most about 15% w/w such as, e.g., at the most about10% w/w or at the most about 5% w/w.

In a specific embodiment, the invention provides a tablet comprising

i) a calcium-containing compound as an active substance,ii) a vitamin D, andiii) optionally one or more pharmaceutically acceptable excipients oractives.

More specifically, the tablet may comprise

i) at least 200 mg of the calcium-containing compound (normal range200-1500 mg),ii) at least 5 μg of vitamin D (normal range 5-100 μg-1 μg=40 IU), andiii) optionally one or more pharmaceutically acceptable excipients oractives.

In a specific embodiment, the invention provides a tablet comprising

i) from about 50% to about 90% w/w of the calcium-containing compound,ii) from about 0.00029% to about 0.0122% w/w of a vitamin D, andiii) optionally one or more pharmaceutically acceptable excipients oractiveswith the proviso that the total amount of ingredients corresponds toabout 100% w/w.

In particular, the tablet may comprise

i) from about 50% to about 90% w/w of the calcium-containing compound,ii) from about 5 to about 40% w/w of a sweetening agent,iii) from about 0.12% to about 4.9% w/w of a vitamin D including aprotective matrix,iv) optionally one or more pharmaceutically acceptable excipients oractiveswith the proviso that the total amount of ingredients corresponds toabout 100% w/w.

Pharmaceutically Acceptable Excipients

In the present context, the term “pharmaceutically acceptable excipient”is intended to denote any material, which is inert in the sense that itsubstantially does not have any therapeutic and/or prophylactic effectper se. A pharmaceutically acceptable excipient may be added to theactive drug substance with the purpose of making it possible to obtain apharmaceutical composition, which has acceptable technical properties.Although a pharmaceutically acceptable excipient may have some influenceon the release of the active drug substance, materials useful forobtaining modified release are not included in this definition.

The calcium-containing compound and the sugar alcohol may also beadmixed with one or more pharmaceutically acceptable excipients beforeor after roller compaction. Such excipients include those normally usedin formulation of solid dosage forms such as, e.g. fillers, binders,disintegrants, lubricants, flavouring agents, colouring agents,including sweeteners, pH adjusting agents, stabilizing agents, etc.

Typically, a disintegrant is selected from the group consisting of:croscarmellose sodium (a cross-linked polymer of carboxymethylcellulosesodium), crospovidone, starch NF; polacrilin sodium or potassium andsodium starch glycolate. Those skilled in the art will appreciate thatit is desirable for compressible tablets to disintegrate within 30minutes, more desirable within 10 min, most desirable within 5 min;therefore, the disintegrant used preferably results in thedisintegration of the tablet within 30 minutes, more preferable within10 min, most preferable within 5 min.

Examples of disintegrants that may be used are e.g. cellulosederivatives, including microcrystalline cellulose, low-substitutedhydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30);starches, including potato starch; croscarmellose sodium (i.e.cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®);alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g.Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL,Polyplasdone® XL-10); sodium carboxymethyl starch (e.g. Primogel® andExplotab®).

Fillers/diluents/binders may be incorporated such as polyols, sucrose,sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g., spray-driedlactose, α-lactose, β-lactose, Tabletose®, various grades ofPharmatose®, Microtose or Fast-Floc®), microcrystalline cellulose (e.g.,various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 orAvicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® andSolka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose(low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex® 5 and Lodex® 10),starches or modified starches (including potato starch, maize starch andrice starch), sodium chloride, sodium phosphate, calcium sulfate,calcium carbonate.

In pharmaceutical compositions made according to the present invention,especially microcrystalline cellulose, L-hydroxypropylcellulose,dextrins, maltodextrins, starches and modified starches have proved tobe well suited.

In a specific embodiment of the invention, the calcium-containingcompound may be roller compacted together with one or morepharmaceutically acceptable binders, or a binder may be added afterroller compaction. Suitable binders include those normally used withinthe pharmaceutical field although binders usually employed in wetgranulation processes are not likely to be able to function to the sameextent as essentially no liquid is present in during the agglomeration.

More specifically, examples include

cellulose derivates including methylcellulose, hydroxypropylcellulose(HPC, L-HPC), hydroxypropylmethylcellulose (HPMC), microcrystallinecellulose (MCC), sodium carboxymethylcellulose (Na-CMC), etc.;

mono- di-, oligo-, polysaccharides including dextrose, fructose,glucose, isomalt, lactose, maltose, sucrose, tagatose, trehalose, inulinand maltodextrin;

polyols including sugar alcohols such as, e.g., lactitol, maltitol,mannitol, sorbitol, xylitol and inositol;

polyvinylpyrrolidone including Kollidon K30, Kollidon 90F or KollidonVA64 and

proteins including casein.

Glidants and lubricants may be incorporated such as stearic acid,metallic stearates, talc, waxes and glycerides with high meltingtemperatures, colloidal silica, sodium stearyl fumarate,polyethylenglycols and alkyl sulphates.

Surfactants may be employed such as non-ionic (e.g., polysorbate 20,polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61,polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85,polysorbate 120, sorbitane monoisostearate, sorbitanmonolaurate,sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate,sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate andpolyvinylalkohol), anionic (e.g., docusate sodium and sodium laurylsulphate) and cationic (e.g., benzalkonium chloride, benzethoniumchloride and cetrimide) or mixtures thereof.

Other appropriate pharmaceutically acceptable excipients may includecolorants, flavouring agents, and buffering agents.

As appears from the claims, the present invention also provides a methodcomprising the step of processing the particulate material obtained byroller compaction into a solid dosage form. Such dosage forms may beprovided with a coating provided that the coating does not substantiallyretard the release of the active drug substance from the composition.Typically, a film coating may be employed.

Suitable lubricants include talc, magnesium stearate, calcium stearate,stearic acid, hydrogenated vegetable oils and the like. Preferably,magnesium stearate is used.

Suitable bulking agents include xylitol, mannitol, compressible sugars,lactose, calcium phosphate and microcrystalline celluloses.

Suitable artificial sweeteners include dextrose, fructose, glycerin,glucose, isomalt, lactitol, lactose, maltitol, maltose, mannitol,sorbitol, sucrose, tagatose, trehalose, xylitol, alitame, aspartame,acesulfam potassium, cyclamic acid, cyclamate salt (e.g. calciumcyclamate, sodium cyclamate), neohesperidine dihydrochalcone, thaumatin,saccharin, saccharin salt (e.g. ammonium saccharin, calcium saccharin,potassium saccharin, sodium saccharin), and mixtures thereof.

If desired known flavourants and known FD & C colorants can be added tothe composition.

Specific Aspect Relating to Tablets Designed for Dose DispensingMachines

In today's world the global healthcare area faces major changes. Thefuture holds further medical advancement with an increasing elderlypopulation demanding extended care. To improve compliance for e.g. theelderly population, packing of medicine in daily unit/multiple dosepackages (“dose dispensing”) is implemented in more and more countriessuch as, e.g., European countries. Typically the medicine is dosed for atwo weeks period of time and the daily dose package contains e.g.packages/bags for the morning, noon, evening and night medication. Oneach bag information about the person and the medicine are printed.

Development of tablets that are sufficiently robust to be dispensed viaa dose-dispensing machine is a particular challenge when the tablets areformulated as chewable tablets. Normally, chewable tablets do not havesufficient technical properties, which are required for adose-dispensing machine (e.g. the tablets are too fragile and whenexposed to the filling equipment they afford dust which makes thefilling difficult or impossible). Today no product is available on themarket containing a calcium-containing compound as a therapeuticallyand/or prophylactically active substance and being chewable, i.e. havingan acceptable taste and mouthfeel, and at the same time havingsufficient technical properties to enable dispensing via adose-dispensing machine. Accordingly, it is not possible for patients toobtain a daily dose package packed by a dose-dispensing machine, whichpackage includes one or more calcium-containing chewable tablets. Thepresent inventors address this issue by providing a tablet that issufficient robust to withstand packaging by a dose-dispensing machineand at the same time gives the patient or the user the liberty ofchoosing whether she wants to chew, suck and/or swallow the tablet, i.e.the improved technical properties do not impair an acceptable taste andmouthfeel.

As appears from the above, the present invention solves the problem ofproviding chewing tablets with an acceptable taste (which tablets alsomay be sucked or swallowed) and with mechanical properties and a sizethat are suitable for use when the tablets are dispensed by adose-dispensing machine.

In general, improved outcomes and reduced costs are some of theadvantages in applying a dose-dispensing machine, which may be achievedby, e.g.,

i) reduced distribution time, which increases staff efficiency andreleases staff to other functions,ii) reduced incidence of prescribing, dispensing and/or administrationerrors,iii) improved patient care by clearly labelled unit/multi dose packages,which help patients receiving the right medication at the right time,and/oriv) reduced waste of medicine.

As mentioned above, the regulatory requirements for tablets dispensed bya dose-dispensing machine are relative high, and they may be differentfrom country to country with regard to the application, type ofmedicine, stability etc.

Currently, there are three important types of dose-dispensing machineson the market, namely a Tosho machine type Main-Topra 2441 CE. Thismachine doses in small plastic bags and doses up to 244 differentcompositions. Another type Main-Topra 4001 CE doses up to 400 differentcompositions with the same speed as Main-Topra 2441 CE (45 bags/min).

Automed Technologies Inc, USA, has e.g. the type ATC 212 on the Europeanmarket. This machine doses in small plastic bags and doses up to 212different compositions. The machine packs 25 bags/min. Other recenttypes are improved with respect to number of different compositions tobe packed (330 or 520) and the speed is increased to 60 bags/min.

Hyupshin Medical co. Ltd has a dose-dispensing machine, ATDPS, whichdoses in small plastic bags and doses up to 352 different compositions.The speed is 60 bags/min. Furthermore, new machines have been developed(ATDPS JV-500SL and ATDPS JV-352SL), which doses up to 500 differentcompositions with the same speed (60 bags/min).

Due to the different size and shapes of tablets and capsules, themachines are supplied with different types of cassettes and rotaryparts, which ensure that only one tablet or capsule is dosed at the sametime. The main body of the cassettes is well shielded from light, it isdust-tight and damp-proof, so the cassettes are well-suited to store themedicine. Misplacing the cassettes is not possible because of a safetylock. Tablets and capsules will not be stored in the cassettes for morethan a defined period of time to ensure the quality of the compositions.The machines will make a notice when a composition has been stored inthe cassettes for more than this period of time.

With respect to the size of the tablets, the following requirementsshould be met in order to ensure that the tablets can be packed with adose-dispensing machine: The requirements are dynamic and may changeover time.

Round tablet

Length/Diameter

Thickness Distributor Interval Length (mm) Thickness (mm) Tosho MinimumMaximum 14.0 9.4 Hyupshin Minimum 5.5 1.5 Maximum 13.2 6.7 AutomedMinimum 4.6 2.2 Tech. Maximum 14.0 7.0

Oval tablet

Length

Thickness

Width Distributor Interval Length (mm) Thickness (mm) Width (mm) ToshoMinimum Maximum 21.5 7.5 7.5 Hyupshin Minimum 8.5 2.7 4.0 Maximum 20.07.7 10.0 Automed Minimum 6.9 2.2 4.6 Tech. Maximum 21.0 7.5 11.7

The above-mentioned dimension for a round or an oval tablet may bechanged and still fit into the specified dose-dispensing machine.Experiments performed by the present inventors have shown that avariation in a range of ±20% is acceptable, preferable ±10%. Withrespect to the size, one of the major problems, the inventors were facedwith was to reduce the thickness of the tablets. This was solved byusing a proper combination of active ingredient(s) and pharmaceuticallyacceptable excipients and by a careful selection of a suitable particlesize and/or crystal form of the calcium-containing compound, theproperties of the excipients and the preparation method.

It is of importance that the tablets do not create dust and as mentionedabove, the tablets must be sufficiently robust to withstand themechanical stress employed by using a dose-dispensing machine.

The present inventors have found that it is possible to apply a thinfilm coating on the tablets in order e.g. to increase the swallowabilityor in order to minimize any dust problems or problems relating tocrushing strength or friability. To this end it should be noted thatapplication of a film coating cannot repair substantial problems withrespect to crushing strength or friability, but it can just give thefinal push in the right direction. Furthermore, only a thin film coatingmust be applied in order to maintain an acceptable mouthfeel, i.e. thecoating may be applied in an amount that corresponds to an increase inweight of the tablet of at the most about 2% w/w such as, e.g., at themost about 1.5% w/w, at the most about 1% w/w or in a range of fromabout 0.25% to 0.75% w/w based on the weight of the uncoated tablets.

In the following are given dimensions of marketed tablets containingcalcium carbonate Dimensions of calcium carbonate containing tablet

Length Width [mm] Height [mm] [mm] Calcipos-D swallowable (oval/capsule)19.3 5.6  8.7 Calcipos-D chewing tablet (round) 17.2 7.0 — Calcichewchewing tablet (round) 16.1 7.0 — Ideos chewing tablet (quadratic) 19.64.8 19.6

The following non-limiting examples are meant to illustrate the presentinvention.

LEGENDS TO FIGURES

FIG. 1 shows the use of intra granular, extra granular sorbitol or nosorbitol as binder. Investigation of tablet hardness as a function ofcompression pressure.

FIG. 2 shows the impact of compaction force on particle sizedistribution.

FIG. 3 shows the impact on tablet hardness of variations in particlesize distribution of granulate.

FIG. 4 shows the variation in particle size of sorbitol. Investigationof tablet hardness as a function of compression pressure.

FIG. 5 shows the variation in amount of sorbitol and addition ofmicrocrystalline cellulose. Investigation of tablet hardness as afunction of compression pressure.

FIG. 6 shows the impact of moisture content of surrounding air on tablethardness.

FIG. 7 shows the impact on tablet hardness of addition of other sugaralcohols, that is maltitol.

FIG. 8 shows the impact on tablet hardness of omitting lumb breaking of38 μm sorbitol.

FIG. 9 shows the variation in granulate pad. Investigation of impact onvitamin D₃ Vitamin assay in samples drawn during tabletting.

FIG. 10 shows the impact on tablet hardness of admixing of Povidone K30.

FIG. 11 shows the impact of type and particle size of sugar alcohol.Scoralite is used as calcium source.

FIG. 12 shows the impact of type and particle size of sugar alcohol.Merck 2064 is used as calcium source.

FIG. 13 shows the impact of extra granular admixture of sortitol indifferent particle sizes. Scoralite is used as calcium source.

FIG. 14 shows the impact of granular particle size of intra or extragranular admixture of sorbitol. Scoralite is used as calcium source.

FIG. 15. SEM photos of regularly shaped calcium carbonate crystals(Merck 2064 and Scoralite, respectively)

FIG. 16. SEM photos of sugar alcohols having a micro structure (isomaltand sorbitol, respecitvely)

FIG. 17. SEM photos of sugar alcohols that do not have a micro structure(maltitol, xylitol and mannitol, respectively)

FIG. 18. SEM photos of roller compacted material consisting of Scoraliteand sorbitol and Merck 2064 and xylitol, respectively.

FIG. 19. Compaction properties of sugar alcohols.

FIG. 20. Stability using Scoralite 1B.

FIG. 21. Stability using Merck 2064.

FIG. 22. Impact of mixing time on crushing strength stability

FIG. 23. DVS Mass plot showing the water up-take in the presence andabsence of a superdisintegrant.

FIG. 24 shows suitable design and dimensions of a tablet according tothe invention.

FIG. 25 shows how to break a tablet into two parts of essentially thesame size by providing a pressure at both ends. The tablet has a designas shown in FIG. 24.

List of materials Raw material Trade name Vendor Calcium carbonateScoralite 1B Scora Watrigant, SA, France Merck 2064 Merck, Darmstadt,Germany Sorbitol Neosorb P100T Roquette Freres, France Mean particlesize: 110 μm (coarse) Sorbidex P1666BO Cerestar Mean particle size: 38μm (fine) Sorbidex P16656 Mean particle size: 300 μm Xylitol XylitolCM50 Danisco Sweeteners Isomalt Isomalt ST-PF: 28 μm Palatinit GmbH,(fine) Mannheim, Germany Isomalt DC100: 137 μm (coarse) MannitolMannitol 60 Roquette Freres, France Maltitol Maltisorb P90 RoquetteFreres, France Povidone K 30 Povidone K 30 BASF Povidone K 90 Povidone K90 BASF Cellulose Microcrystalline Cellulose Microcrystalline MingtaiChemical, Taiwan Type M101 Type M101 Pregelatinized Maize Starch 1500Colorcon Starch Crosscarmellose Sodium Primellose DMV InternationalAcesulfame Potassium SweetMaster Ace Fine Brøste A/S, Denmark GradeFlavour lemon Flavour Lemon Powder Firmenich, Schwitzerland Flavourgranulate lemon Nycomed Flavour granulate orange Nycomed AspartameAjinomoto powder Multi Chem Wallinco (Norway) D3 vitamin D3-vitamin,Cholecalciferol Roche 100 Magnesium Stearate Magnesium stearate PeterGreven, Netherlands Hypromellose 15 Methocel E15 Dow Talc Talc Luzenac,Italy Propylene glycol Propylene glycol Lyondell Chemie, France Glyceroldistearat Type I EP Precirol ATO 5 Gattefossé, France

EXAMPLES Example 1 Investigation of the Influence on Tablet Strength ofIntra-Granular Admixing of Sorbitol

The investigations were based on the following formulation:

TABLE 1 Formulation 1 Calcium Carbonate (Scoralite) 71.40% 2 Sorbitol(110 μm) 22.28% 3 Povidone K30 2.08% 4 Aspartame 0.06% 5Cholecalciferol - sieved 250 μm (Vitamin D₃) 0.25% 6 Flavour granulateorange 3.60% 7 Magnesium Stearate 0.34%

Sorbitol was lump breaked in a Cone Mill (Quadro U20) and afterwardspremixed with Calcium Carbonate in a high-shear mixer (Diosna P250 atlow impeller speed and no chopper) for 60 sec.

The premix was granulated on a roller compactor (Gerteis 3W-Polygran),and the compacted granules was then mixed with Povidone K30, Aspartame,D₃ Vitamin and Flavour in a high-shear mixer (Diosna P250 at lowimpeller speed and no chopper) for 60 sec. Finally, lubrication withMagnesium Stearate was done a high-shear mixer (Diosna P250 at lowimpeller speed and no chopper) for 25 sec.

The roller compaction was based on a setup with knurled rollers andcontrol. The key set up parameters are: Gap Width (GW), Force (F),Roller Speed (RS) and screen size.

The particulate material obtained was a granulate that was tabletted ona Fette PT1090 fully instrumented tablet press with a 16 mm roundstandard concave tablet design. Tablet weight was approximately 1,750mg. All in-process weight and hardness data are obtained using aSchleuniger AT4.

In this example conditions for the roller compaction was the following:

TABLE 1 Roller compaction conditions H314301 H310001 sb. 10 sb. 02H314301 sb. 08 GW, mm 3.5 2.0 3.0 F, kN/cm 12 8 20 RS, rpm 10 5 5 Screensize, mm 1.5 1.5 1.5 Sorbitol admixed Intra granular Extra granularExtra granular

The impact on tablet hardness of having admixed sorbitol (having a meanparticle size, determined by use of a Malvern laser sizer, of approx 110μm) compared to not admixing the sorbitol is shown in FIG. 1.

In FIG. 1 it is shown that the presence of sorbitol leads to increasedtablet hardness values when compared to tablets consisting solely ofcalcium carbonate. Furthermore, it is illustrated that admixing thesorbitol 110 μm intra- or extra granular has the same impact on tablethardness.

Example 2 Impact on Tablet Strength of Variation in Roller CompactionForce

This experiment was carried out according to Example 1 with thevariations as described in Table 2.

TABLE 2 The actual values for GW, F, RS and screen size H326501 sb. 3H326501 sb. 07 H326501 sb. 11 GW, mm 4.0 4.0 4.0 F, kN/cm 4 8 12 RS, rpm15 15 15 Screen size, mm 1.5 1.5 1.5

Furthermore, the sorbitol had a mean particle size around 38 μm.

The resulting particle size distribution and hardness profiles are shownin FIGS. 2 and 3.

From FIGS. 2 and 3 it is illustrated that even though a variation inroller compaction force leads to a variation in particle size, thetablet hardness profiles remain unaltered. However, an increase incompaction force will improve flowability of the granulate due to areduction in the fraction below 125 μm.

Example 3 Impact on Tablet Strength of Variation in Particle Size ofSorbitol

This experiment was carried out according to Example 1 with thefollowing variations:

The actual values for GW, F, RS and screen size were the following:

GW 3.5 mm,

F 12 kN/cm,RS 10 rpm,Screen size 1.5 mm.

Three qualities of sorbitol was used, having mean particle sizes around11 μm or 38 μm or 110 μm. The 11 μm and 38 μm qualities were obtained bymilling the 110 μm quality.

The tablet design was 14 mm round concave with double radius.

The impact of the variations in particle size of sorbitol is shown inFIG. 4.

From FIG. 4 it is seen that decreasing the size of sorbitol leads tomarkedly increased tablet hardness for fixed compression force.

Example 4 Impact on Tablet Strength of Variation in Intra-GranularConcentration of Sorbitol and Presence of Microcrystalline Cellulose

This experiment was carried out according to Example 1 with thefollowing variations as described in Table 3 and Table 4. The rollercompaction were in all cases carried out on calcium carbonate andsorbitol alone, where after the other excipients listed were admixed.

TABLE 3 The formulation used H335528 H404302 H407504 Calcium carbonate,Scoralite 67.5% 71.4% 80.1% Sorbitol, 38 μm 21.1% 22.3% 15.5% Mixingratio - Calcium:Sorbitol 3.2:1 3.2:1 5.2:1 Cellulose MicrocrystallineType 6.6% M101 Starch 1500 4.2% 3.4% Acesulfam Potassium 0.1% 0.1%Flavour Lemon 0.3% 0.5% Povidone K30 2.1% Aspartame 0.1% Vitamin D3 0.3%Flavour granulate orange 3.6% Magnesium stearate 0.3% 0.3% 0.4%

TABLE 4 The actual values for GW, F, RS and screen size H335528 H404302H407504 GW, mm 3.5 4.0 3.5 F, kN/cm 12 12 12 RS, rpm 15 15 3 Screensize,mm 1.5 1.5 1.5

FIG. 5, which includes batch H310001 sb10 from Example 1 shows theimpact on tablet hardness when the amount and particle size of sorbitolused are varied. This illustrates that it is important to have sorbitoldistributed as completely as possible between the calcium particles.Inappropriate distribution will be the result of too large a particlesize or too low a concentration. Furthermore, FIG. 5 illustrates thatthe impact of cellulose microcrystalline (mcc) on tablet hardness isminor compared to the influence of sorbitol.

Example 5 Impact on Tablet Strength of Moisture Content in theSurrounding Air when Using Sorbitol as Binder

This experiment was carried out according to Example 1 with thefollowing variations as described in Table 5.

TABLE 5 The actual values for GW, F, RS and screen size H310001 H315501H322801 sb. 02 sb. 11 sb. 02 dried GW, mm 3.5 3.5 3.5 F, kN/cm 12 16 12RS, rpm 10 10 10 Screen size, 1.5 1.5 1.5 mm

Further, the tablet design was 14 mm round concave with double radius.

The manufacturing was carried out during winter and summer conditions.During winter condition RH in the surrounding air was below 50%, whereasin the summer period the RH was above 70%.

The impact on tablet hardness of variation in moisture content in thesurrounding air is shown in FIG. 6.

FIG. 6 shows that the granulate is very sensitive to moisture, whensorbitol having a mean particle size of 110 μm is used.

Tablets based on sorbitol having a mean particle size of approx. 38 μmdid not show sensitivity towards the time of the year at which thetabletting was carried out.

Example 6 Bulk Density of Roller Compacted Formulations Containing aCalcium Salt

Changes in bulk density as a consequence of roller compaction are shownin Table 6.

TABLE 6 Changes in bulk density Density roller compacted Density mixturegranulate (g/cm³) (g/cm³) 0.99 1.08

Based on data in the table above it is clear that the increase indensity caused by the roller compaction process is minimal.

This experiment was carried out according to Example 1 with thefollowing variations:

-   -   Only the granulate was produced. The admixing of povidone 30,        aspartame, D3 vitamin and flavour was omitted.    -   The actual values for GW, F, RS and screen size were the        following

GW, mm 3.5 F, kN/cm 12 RS, rpm 10 Screen size, mm 1.5

Example 7 Influence of Variations in the Type of Binder Used on TabletHardness

This experiment was carried out according to Example 1 with thefollowing variations as described in Table 7 and Table 8. The rollercompaction was in all cases carried out on calcium carbonate and eithersorbitol or maltitol, where after the other excipients listed wereadmixed.

TABLE 7 The formulation used H335525 H335528 Calcium carbonate,(Scorallite) 75.3% 67.5% Sorbitol, 38 μm 21.1% Maltitol 13.3% Cellulosemicrocrystalline, type M101 6.6% 6.6% Starch 1500 4.2% 4.2% AcesulfamePotassium 0.1% 0.1% Lemon flavour 0.3% 0.3% Magnesium stearate 0.3% 0.3%

TABLE 8 The actual values for GW, F, RS and screen size H335525 H335528GW, mm 3.5 3.5 F, kN/cm 12 12 RS, rpm 3 15 Screen size, mm 1.5 1.5

Further, the tablet design was capsule shaped 9.4 mm*18.9 mm.

The resulting hardness profiles are shown in FIG. 7.

From FIG. 7 it is seen that the use of maltitol as binder does notimpart as good binding properties as that obtained when sorbitol isemployed.

Example 8 Impact on Tablet Hardness of Non-Optimal Admixing of Sorbitol

This experiment was carried out according to Example 1 with thevariations as described in Table 9.

TABLE 9 The actual values for GW, F, RS and screen size were thefollowing: H326501 sb. 11 G334701-a G/H404301 G/H404302 GW, mm 4.0 3.54.0 4.0 F, kN/cm 12 12 12 12 RS, rpm 15 15 15 15 Screen size, 1.5 1.51.5 1.5 mm Sorbitol Yes No Yes Yes lump breaked

Sorbitol had a mean particle size about 38 μm.

FIG. 8 shows the impact on tablet hardness of adding sorbitol that hasnot been lumb breaked before the admixture.

From FIG. 8 it is seen that lump breaking is important. Furthermore,this illustrates the importance of getting an optimal distribution ofsorbitol particles between the calcium particles.

Having an optimal distribution, the tablet hardness is very reproducibleas also shown in FIG. 8.

Example 9 Investigation of D₃ Vitamin Assay of Tablets Based onIntra-Granular Admixing of Fine Particle Sized Sorbitol

This experiment was carried out according to Example 1 with thevariations as described in Table 10.

TABLE 10 The actual values for GW, F, RS and screen size H328001 sb. 01H328001 sb. 02 GW, mm 4.0 4.0 F, kN/cm 8 12 RS, rpm 15 15 Screen size,mm 1.25 1.5

Sorbitol had a mean particle size around 38 μm.

In FIG. 9 the D3 vitamin assay results from sampling over 2 hours ofcompression has been illustrated. It can be seen that the admixing of asmall amount of D3 vitamin is possible in production scale. The slopesof the trend lines are close to 0 and almost identical for the 2 batchestested in this example.

Example 10 Impact on Tablet Hardness of the Admixing of the BinderPovidone K 30, a Typical Example of a Wet Binder

This experiment was carried out according to Example 1 with thevariations as described in Table 11 and Table 12.

TABLE 11 The actual values for GW, F, RS and screen size H310002 sb.H310002 sb. H310003 sb 17 19 17 H310003 sb 19 GW, mm 3.5 3.5 3.5 3.5 F,kN/cm 8 8 8 8 RS, rpm 10 10 10 10 Screen size, 1.5 1.5 1.5 1.5 mm

TABLE 12 Changes of the composition and tabletting H310002 sb. 17H310002 sb. 19 H310003 sb 17 H310003 sb 19 +/−Povidone + + − − K 30Tablet design 16 mm 14 mm 16 mm 14 mm round, concave round, concaveround, concave round, concave double radius double radius

FIG. 10 shows that the admixing of dry Povidone K 30 has no beneficialimpact on the tablet hardness.

Example 11 Impact on Tablet Hardness of Variation in Type of CalciumCarbonate and Type and Particle Size of Sugar Alcohol

This experiment has been carried out as described below:

In all the below described experiments 1-24 the amount of calcium saltis 76.22% w/w of the final tablet mass, the amount of sugar alcohol is23.78% w/w, with the exception of experiments 4 and 20 at which the23.78% w/w of sugar alcohol is replaced with 14.63% w/w of sugar alcoholand 9.15% w/w of Precirol. The actual type of calcium source and thetype of sugar alcohol is described in Table 13.

TABLE 13 types of calcium and sugar alcohol source Experiment Calciumsalt Sugar alcohol, Sugar alcohol no.: Source source and ps* Figurelegend 1 Scoralite Sorbitol, 38 μm Sorb38 2 Scoralite Sorbitol, 110 μmSorb110 3 Scoralite Xylitol, 34 μm Xyli34 4 Scoralite Xylitol, 34 μm andPrecirol Xyli34P 5 Scoralite Isomalt, 28 μm Isom28 6 Scoralite Isomalt,137 μm Isom137 7 Scoralite Mannitol, 48 μm Mann48 8 Scoralite Maltitol,31 μm Malt31 17 Merck 2064 Sorbitol, 38 μm Sorb38 18 Merck 2064Sorbitol, 110 μm Sorb110 19 Merck 2064 Xylitol, 34 μm Xyli34 20 Merck2064 Xylitol, 34 μm and Precirol Xyli34P 21 Merck 2064 Isomalt, 28 μmIsom28 22 Merck 2064 Isomalt, 137 μm Isom137 23 Merck 2064 Mannitol, 48μm Mann48 24 Merck 2064 Maltitol, 31 μm Malt31 25 Scoralite Sorbitol,approx. 300 μm Sorb300 26 Scoralite Sorbitol, 38 μm Sorb38 *ps: meanparticle size (d(v; 0.5) determined by use of a Malvern Mastersizer)

The calcium salt and the sugar alcohol are mixed in a total amount of 6kg in a Fielder high shear mixer. The sugar alcohol is sieved throughsieve size 300 μm prior to mixing. The mixing of 6 kg is done twice andthe total yield of 12 kg is mixed in a planetary mixer. Thereafter, themixtures are roller compacted (intra granular sugar alcohol) using thefollowing values for GW, F, RS and screen size. (For the experiments25-26 the sugar alcohol is admixed by hand after roller compaction hasbeen carried out (extra granular sugar alcohol)).

GW: 3.5 mm F:  12 kN/cm RS:   5 rpm Screen size 1.5 mm

The compactate is admixed with 0.34% w/w of magnesium stearate.

Compression is carried out on a Fette 1090 using a 18.9 mm×9.4 mmcapsule shaped punch design and a theoretical tablet mass of 1683 mg.For each experiment a correlation between tablet compression force andcrushing strength is found. The crushing strength has been measured byuse of a Schleuniger Autotest 4 and n=20. The resulting hardnessprofiles are shown in FIGS. 11-13.

From FIGS. 11-12 it is seen that for both the Scoralite and Merck 2064calcium carbonates intra granular admixed fine particular sorbitol orisomalt results in tablets with a much higher crushing strength than canbe obtained with xylitol, mannitol, maltitol or coarse particularsorbitol and isomalt. Furthermore it was observed during the experimentthat the use of mannitol, xylitol or maltitol leads to tablets with atendency of capping.

Without being bound by theory the impact of different sugar alcohols ontablet crushing strength can be described as being dependent on theirbinding properties and distribution throughout the tablet. Thedistribution of the sugar alcohol throughout the tablet is crucial, asregular shaped calcium carbonate crystals, see FIG. 15, are not likelyto establish the adherence necessary for obtaining a coherent tablet.Sugar alcohols capable of obtaining a homogeneous distributionthroughout the tablet are especially suitable. Examples of such sugaralcohols are sorbitol and isomalt as illustrated in FIG. 16 where it isshown that the individual crystals of sorbitol and isomalt have a microstructure or a non-compact micro structure, i.e. the individual crystalshave some deformation capacity to be squeezed between other kinds ofparticles. This is in contrast to the crystals of mannitol, maltitol andxylitol where the same kind of micro structure cannot be found, asillustrated in FIG. 17. This micro structure is assumed facilitate afurther distribution throughout the tablet by breakage during the tabletcompression. The distribution of sugar alcohol made possible by thismicro structure is shown in FIG. 18. Therefore, calcium carbonatecontaining tablet comprising sugar alcohols with the described microstructure are much more likely to be coherent tablets, with asatisfactory crushing strength, than tablet based on sugar alcoholswithout the described micro structure.

However, even if a micro structure is present it is required that theparticles of the sugar alcohols are sufficiently small which isillustrated in FIGS. 11 and 12 where it can be seen that fine particularsorbitol and isomalt results in tablets with a much higher crushingstrength than can be obtained with coarser particles.

Based on the above discussions of the importance of particle size andmicro structure of sugar alcohols the results shown in FIG. 13 caneasily be explained. Even though tablets illustrated by the curveSorb300 are based on the teaching of Pharmaceutical Technology Vol 1(Tabletting technology, editor M. H. Rubinstein), where instant sorbitolhaving a particle size distribution of 60-90% between 212-500 μm isadmixed as extra granular sugar alcohol, the crushing strength isextremely low even at high compression forces. Crushing strength can bemarkedly increased by the use of sorbitol with a finer particle size,see FIG. 13 (curve Sorb38). Even though the different punch design ofExample 1 makes a direct comparison difficult it is illustrated thanwhen using sorbitol of a 110 μm quality there is no difference betweenintra and extra granular admixture of sorbitol. Therefore, when usingsorbitol as extra granular sugar alcohol the particle size is verycritical. This also applies for other sugar alcohols.

However, the compaction of pure calcium carbonate results in a granulatewith a very low binding capacity, as illustrated by the very largefraction below 125 μm seen in FIG. 14. This means that by adding sugaralcohol extra granularly instead of intra granularly the final mixturefor tabletting will have extremely poor flow properties which will maketabletting in production scale very difficult.

Furthermore it can be seen from FIG. 11 that the addition of Precirolincreases the crushing strength without changing the sensitivity of thecrushing strength to changes in main compression force, that is Precirolis less optimal as a binder.

Example 12 Test of Compactability of Different Sugar Alcohols

Tablets comprising sorbitol 110 μm, sorbitol 38 μm, isomalt 27 μm,maltitol, mannitol or xylitol were compressed on an instrumented FetteExacta 1/F single punch tablet press, only maximum compression force onthe upper punch was recorded. Before the compression of each tablet thepunch tips and the die bore were lubricated with a 5% suspension ofmagnesium stearate in acetone. The acetone was allowed to evaporatebefore compression of the tablet.

The sugar alcohol was weighed, transferred to the die bore and thencompressed, see Table 14. Immediately after ejection the tablet wastested for crushing strength.

TABLE 14 Sugar alcohol Trade name Tablet weight Sorbitol Neosorb P100T530 mg Sorbidex 400 mg P1666BO Isomalt Isomalt ST-PF 400 mg MaltitolMaltisorb P90 400 mg Mannitol Mannitol 60 400 mg Xylitol Xylitol CM50400 mg

It was assumed that the obtained tablet crushing strengths of the sugaralcohols are substantially independent of particle size and this wastested using sorbitol having two different mean particle sizes, 38 μmand 110 μm. From FIG. 19 (each point is the average of threemeasurements) it is seen that the assumption was correct. Therefore,test of particle size was not repeated for the other sugar alcohols.

From FIG. 19 it can be seen that sorbitol has the best compactabilityresulting in the steepest slope of the correlation between compressionforce and crushing strength. Sorbitol is followed by isomalt whereasmaltitol, mannitol and xylitol have a very poor compactability. Theseresults support the results discussed in Example 11 and FIGS. 17-18.Therefore, it can be concluded that sugar alcohols having a polycrystalstructure results in stronger tablets when compressed than sugaralcohols without a polycrystal structure.

Example 13 Impact on Tablet Crushing Strength Stability of Variation ofCalcium Carbonate and Type and Particle Size of Sugar Alcohol

Tablets according to Example 11 were manufactured. Tablets with aninitial crushing strength between 70 N to 100 N were stability tested.The conditions for the stability testing were storage in open petridishes at 25° C./60% (25/60) relative humidity (RH) for 14 days. Thecrushing strength was tested just before the stability test was startedand after 2 days, 7 days and 14 days. The crushing strength was measuredby use of a Schleuniger-2E Hardness tester, n=10.

Crushing strength stability is shown in FIGS. 20-21.

From FIGS. 20 and 21 it is seen that for both the Scoralite and Merck2064 calcium carbonates intra granularly admixed fine particularsorbitol or isomalt (both fine and coarse) results in tablets with asatisfactory stability of crushing strength. However the use of coarsesorbitol results in tablets with a decrease in crushing strength duringstorage in open petri dishes at 25° C./60% RH.

Possible explanations for the observed differences in stability oftablets containing coarse sorbitol or either fine sorbitol or isomalt(both fine and coarse) could be the following: In order to obtainsorbitol containing tablets with the desired initial crushing strength aconsiderably higher main compression force was needed for tabletscontaining coarse sorbitol compared to fine. Even though the tabletsbased on coarse sorbitol were less porous, the crushing strengthdeclined considerably during the first two days of stability testing.This could be caused by a much less homogeneous distribution of thecoarse sorbitol in the tablet.

For isomalt the use of either fine or coarse particles in both casesleads to tablets with satisfactory crushing strength stability. Thiscould be caused by the fact that isomalt is considerably lesshygroscopic compared to sorbitol.

Example 14 Manufacture of Calcium Carbonate Containing Tablets

Tablets were manufactured according to Example 1 with the belowdescribed exceptions. The roller compaction was in all cases carried outon calcium carbonate and sorbitol, where after the other excipientslisted were admixed. The film liquid was applied at described below.

Tablet formulation:

TABLE 15 Amount per tablet 2 [mg] [%] 3 [mg] [%] Raw material Calciumcarbonate Scoralite 1250 72.2 1250.0 71.9 Sorbitol P 1666B0 385.5 22.3385.5 22.2 Cellulose microcryst Type 101 75 4.3 75 4.3 AcesulfamPotassium 1 0.1 1 0.1 Flav. Lemon Powder 7.5 0.4 Magnesium stearate 60.3 6 0.3 Tablet weight [mg] 1717.5 1725.0 Film liquid* Hypromellose 157.16 0.4 7.19 0.4 Talc 4.30 0.2 4.31 0.2 Propylene glycol 1.43 0.1 1.440.1 Water, purified 130.28 130.81

The granulate was compressed on a Fette PT1090 using capsule shapedpunches (9.4 mm×18.9 mm).

The film liquid were applied on the tablets in an Accella Coater 150(Manesty Inc.), by use of the following parameters:

Inlet air temperature 50° C. Outlet air temperature 45° C. Pan rpm 2.2batch size 75 kg

-   -   The obtained tablets had a crushing strength of 133 N and a        disintegration time below 12 minutes.

Example 15 Manufacture of Calcium Carbonate Containing Tablets

A granulate was manufactured according to Example 14 with the followingexceptions:

TABLE 16 Amount per Amount per tablet [mg] tablet [%] Raw materialCalcium carbonate, Scoralite 1250.0 72.26 Sorbitol 38 μm 385.0 22.26Cellulose microcryst. Type 101 56.0 3.24 Croscarmellose sodium 20.0 1.16Magnesium stearate 6.0 0.35 Acesulfame Potassium 1.0 0.06 Flavour lemonpowder 7.5 0.43 D3-vitamin 4.4 0.25 Total 1729.9 100.00 Coating liquidHypromellose 15 7.2 Talc 4.3 Propylene glycol 1.4 Water, purified 131.2Total 1742.9

The granulate was compressed on a Fette PT 2090 using capsule shapedpunches (9.4 mm×18.9 mm).

The tablets were coated in an O'Hara FC-660 (O'Hara), by use of thefollowing parameters:

Inlet air temperature 50° C. Product temperature 45° C. Pan rpm 2.0Process air flow 8000 m³ Liquid flow rate 300 g/min batch size 600 kg

-   -   The obtained tablets had a crushing strength of 135 N and a        disintegration time below 2 minutes.

Example 16 Impact on Sensoric Properties of the Use of Sugar Alcoholsand Flavours Kalcipos®-D

Ingredients according to the manufacturer:

-   -   Calcium carbonate    -   Vitamin D₃    -   Maltodextrin    -   Crosscarmellose sodium    -   Gelatine    -   Sucrose    -   Maize starch    -   Colloidal silicium dioxide    -   Magnesium stearate    -   Hypromellose    -   Macrogol 6000    -   Parafin    -   Hydrated soya bean oil    -   Hydrated cottonseed oil

Sensorial comparison has been performed between the above describedKalcipos®-D and tablets manufactured as described in Example 15.

The test has been performed as a paired comparison test in accordancewith ISO-5495, by use of 8 trained persons. This will show whether thereis a significant difference between the reference (Kalcipos®-D) and thetablets of Example 15, at a five % level.

The products have been compared with respect to the followingproperties:

-   -   Sweetness    -   Lemon flavour    -   Chalkiness

The results conformed a significant difference with respect to all threeproperties showing more sweetness, more lemon flavour and lesschalkiness for the tablets of Example 15 when compared to Kalcipos®-D.

Example 17 Manufacture of Calcium Carbonate Containing Tablets

Tablets were manufactured according to Example 14 with the followingformulations:

TABLE 17 Raw material [% w/w] Calcium carbonate, Scoralite 60-94Sorbitol 38 μm or Isomalt 27 μm  5-30 Cellulose microcryst Type 101 0-10 Crosscarmellose sodium 0-5 Acesulfam Potassium 0.1 Flav. LemonPowder 501162 0-2 Magnesium stearate 0.3-1  

The individual amounts are adjusted so that each composition contains1250 mg calcium carbonate and that the total amount does not exceed100%. Tablets are compressed by use of punch design like:

-   -   Round shallow concave 16 mm    -   Round compound cup 14 mm    -   Capsule shaped 9.4×18.9 mm    -   Capsule shaped 8.6×18.9 mm        on a Fette PT 2090 achieving tablets with a crushing strength        above 70 N and a disintegration time below 15 minutes for        tablets containing croscarmellose sodium in an amount of        approximately 0.5% or more (such tablets are meant for the oral        route by swallowing). Optionally a standard water soluble coat        (such as a traditional coating known by a person skilled in the        art) can be applied to the tablets, in which case the        disintegration time should be below 30 minutes.

If tablets only are meant for chewing the disintegration time is notrelevant.

Example 18 Investigation of the Impact of Different Production Methodson the Size of Calcium Carbonate Tablets

This experiment was carried out in large production with a batch size ofapprox. 40.000 tablets. The experiment was performed in order toinvestigate whether the technique used for manufacturing granulate forthe product had any impact on tablet dimensions especially the tabletheight.

The techniques in question were:

i) Fluid bed granulation, andii) Roller compaction.

Roller compaction Fluid bed Batch 2 Batch 1 per 1000 tabl. per 1000tabl. Raw material [g] [g] I Calcium carbonate 1250.0 1250.0 ScoraliteII Sorbitol 38 μm — 385.5 III Sorbitol 110 μm 390.0 — IV Povidone K 9036.4 — V Cellulose — 75.0 microcrystalline Type 101 VI Acesulfam — 1.0Potassium VII Aspartame 1.0 VIII Flavour lemon — 7.5 IX Flavourgranulate 50.68 — lemon X Magnesium stearate 6.0 6.0 XI Purified water73.0 — Tablet weight 1734.08 1725.0

Manufacture of Batch 1:

The granulating fluid is manufactured by dissolving IV in XI. III ispassed through a suitable screen and mixed with I in a Glatt fluid bedgranulator. The powder mixture is granulated by spraying the granulatingfluid on the powder bed while the fluidizing process is ongoing. Theremaining parts of the excipients VII, IX and X are admixed to granulateand tablets are compressed by use of a Fette PT1090 and capsule shapedpunch design (9.4×18.9 mm).

Manufacture of Batch 2

II is passed through a suitable screen and mixed together with I in a220 I high shear mixer for 1 min at impeller speed 110 rpm and chopperspeed 1500 rpm.

The powder mixture is granulated using a roller compactor according toexample 1. The remaining excipients V, VI, VIII and X are admixed by usea high shear mixer (Diosna P250) with low impeller speed no chopper for60 seconds and finally tablets are compressed by use of a Fette PT1090and capsule shaped punch design (9.4×18.9 mm).

Tablet Tablet Compression height length force [kN] [mm] [mm] Batch 119.9 7.40 19.04 Batch 2 20.9 7.16 19.07

Comparison of batch 1 and 2 shows that the lowest tablet height isobtained by roller compaction.

Example 19 Stability of Calcium Carbonate Tablets

This experiment was carried out in large production with a batch size ofapprox. 693,000 tablets. 3 batches were manufactured.

The experiment was performed in order to investigate the stability ofcoated tablets in open petri dishes and the reproducibility of crushingstrength for three mixing intervals.

Composition: Amounts per tablet

TABLE 18 [mg] [%] Raw material Calcium carbonate, Scoralite 1250 72.26Sorbitol 38 μm 385 22.26 Cellulose microcrystalline, type M101 56.0 3.24Crosscarmellose sodium 20.0 1.16 Acesulfam Potassium 1.0 0.06 FlavourLemon 7.5 0.43 D3 vitamin 4.4 0.25 Magnesium stearate 6.0 0.35 Tabletweight [mg] 1729.9 Coating Hypromellose 15 7.2 Talc 4.3 Propylene glycol1.4 Water, purified 131.2 Total weight [mg] 1742.9

The batch was manufactured according to the following description:

Premixing and Roller Compaction

Calcium Carbonate is added to a tumble mixer.

Sorbitol is sieved through screen size 2.0 mm and is transferred to thetumble mixer Calcium carbonate and sorbitol are premixed in the tumblemixer. Mixing time 15 minutes, speed 6 rpm.

The pre-mix is roller compacted with knurled rollers, screen size 1.5mm. Settings: Gap 3.5 mm, Force 12 kN/cm, Roller speed 15 rpm.

Mixing

The rest of the excipients, with the exception of magnesium stearatewere admixed to the granulate in a tumble mixer using speed 6 rpm andmixing time for the 3 batches were according to Table 19.

TABLE 19 Mixing intervals Batch 1 Batch 2 Batch 3 Mixing time 20 minutes30 minutes 40 minutes

Magnesium stearate were admixed for 5 minutes, speed 6 rpm.

Tabletting

The granulate is compressed on a Fette 2090 tablet press by use of acapsule shaped punch design (18.9×9.4 mm) achieving a crushing strengthof 110 N.

Coating

Coating parameters is as described in Example 15.

The amount of film applied is corresponding to a theoretical weight gainof 0.75%.

Stability studies in open petri dishes stored at 25° C./60% RH have beenperformed. The results are shown in FIG. 22. Even though sorbitol havinga mean particle size of 38 μm has been used a decrease is seen. Thisdecrease is similar to that of tablets based on sorbitol 110 μm fromExample 13. The decrease is due to the addition of extra excipients.However, the crushing strength is still sufficiently high to allowhandling and therefore acceptable.

Example 20 Impact of Super Disintegrant on Water Absorption

A mixture of 72.26% calcium carbonate (Scoralite) and 22.26% sorbitol(38 μm) were Roller compacted as described in Example 18.

The roller compacted granulate was admixed the following ingredients:

TABLE 20 Composition of test 1 and 2 based on content of single tablets:Excipients Test 1 Test 2 I Roller compacted granulate 1635.5 mg 1635.5mg from example 18 II Cellulose microcrystalline  75.0 mg  75.0 mg Type101 III Croscarmellose  17.3 mg sodium VI Magnesium stearate   6.0 mg  6.0 mg Tablet Weight: 1733.8 mg 1716.5 mg

Tablets are compressed by use of capsule shaped punch design (9.4×18.9mm)

Coating of the tablets is carried out based on the following composition

Excipients % (w/w) I Hypromellose 15 2.5 II Talkum 1.5 III PropyleneGlycol 0.5 IV Purified water 95.5

Coating is carried out in a lab scale coater (Combi Cota, Niro, Denmark)using the following parameters:

Inlet air temperature: 48-50° C.Liquid flow rate 3-4 gram/minSpray pressure: 2 bar

The tablets were tested in a DVS (Dynamic Vapour Sorption) equipment(Surface Measurement System, UK) at 25° C. and 60% RH. Each test wasbased on 5 tablets. The result is shown in FIG. 23. From FIG. 23 it canbe seen that the addition of a superdisintegrant only results in a minorincrease in water absorption meaning that only minor impact on stabilityof tablet technical properties is to be expected from the addition of asuperdisintegrant.

1-75. (canceled)
 76. A particulate material comprising one or moreregularly shaped calcium-containing compounds as an active substance andone or more pharmaceutically acceptable sugar alcohols having a microstructure, wherein the one or more sugar alcohols have a mean particlesize of at the most about 150 μm.
 77. A particulate material accordingto claim 76, wherein the pharmaceutically acceptable sugar alcohol—whencompressed into tablets containing 100% w/w of the sugar alcohol—has aslope of correlation between crushing strength (measured in N) andcompression pressure (measured in N) of 7×10³ or more.
 78. A particulatematerial according to claim 76, wherein the pharmaceutically acceptablesugar alcohol has binding properties.
 79. A particulate materialaccording claim 76, wherein the one or more calcium-containing compoundis in the form of crystals having a specific surface area below 1.5m²/h.
 80. A particulate material according to claim 76, wherein theconcentration of the pharmaceutically acceptable sugar alcohol in theparticulate material is at least about 5% w/w.
 81. A particulatematerial according to claim 76, wherein the pharmaceutically acceptablesugar alcohol employed has a mean particle size in a range of from about5 to about 150 μm.
 82. A particulate material according to claim 76,wherein the sugar alcohol is sorbitol or isomalt or mixtures thereof.83. A particulate material according to claim 82, wherein the sugaralcohol is sorbitol.
 84. A particulate material according to claim 83,wherein the mean particle size is in a range of from about 25 to about50 μm.
 85. A particulate material according to claim 82, wherein thesugar alcohol is isomalt.
 86. A particulate material according to claim85, wherein the mean particle size is in a range of from about 20 toabout 50 μm.
 87. A particulate material according to claim 85 comprisinga sugar alcohol selected from the group consisting of mannitol, xylitol,maltitol, inositol, lactitol, and mixtures thereof.
 88. A particulatematerial according to claim 76 comprising a mixture of sorbitol andxylitol.
 89. A particulate material according to claim 88, wherein theweight ratio between sorbitol and xylitol is in a range of from about1:0.1 to about 1:1.5.
 90. A particulate material according to claim 76comprising a mixture of isomalt and xylitol.
 91. A particulate materialaccording to claim 90, wherein the weight ratio between isomalt andxylitol is in a range of from about 1:0.1 to about 1:1.5.
 92. Aparticulate material according to claim 76 wherein thecalcium-containing compound is a calcium salt.
 93. A particulatematerial according to claim 76 wherein the calcium salt is calciumcarbonate.
 94. A particulate material according to claim 93 whereincalcium carbonate has a shape and a mean particle size corresponding tothat of Scoralite 1B or Merck
 2064. 95. A particulate material accordingto claim 94 wherein calcium carbonate is Scoralite 1B or Merck
 2064. 96.A particulate material according to claim 76 wherein the content of thecalcium-containing compound in the particulate material is in a range offrom about 40% to about 100% w/w.
 97. A particulate material accordingto claim 76 wherein a SEM photo of the particulate material—whencompressed into a tablet—shows that a surface of a deformed particle ofthe pharmaceutically acceptable sugar alcohol is in close contact withsurfaces of the crystals of the one or more calcium-containing compound.98. A particulate material according to claim 76 further comprising oneor more pharmaceutically acceptable excipients or additives, or one ormore therapeutically, prophylactically and/or diagnostically activesubstances.
 99. A particulate material according to claim 76 furthercomprising vitamins or minerals such as vitamin D or a vitamin K orMagnesium.
 100. A particulate material according to claim 76 comprisingone or more second calcium-containing compounds selected from the groupconsisting of calcium citrate, calcium lactate, calcium phosphateincluding tricalcium phosphate, calcium gluconate, bisglycino calcium,calcium citrate maleate, hydroxyapatite including solvates, and mixturesthereof.
 101. A particulate material according to claim 76 wherein theparticulate material has a flowability such that—when tablets areprepared from the particulate material optionally admixed with at themost 10% w/w of a glidant using a tabletting machine operating at least300 tablets per min.—the mass variation of the tablets obtained fulfilsthe requirements given in Ph. Eur.
 102. A particulate material accordingto claim 101, wherein the dwell time during the preparation of thetablets is at the most about 1 sec.
 103. A particulate materialaccording to claim 76 containing from about 60 to about 95% w/w of thecalcium-containing compound and from about 5 to about 40% w/w of thepharmaceutically acceptable sugar alcohol, provided that the sum doesnot exceed 100% w/w.
 104. A particulate material according to claim 76containing from about 60 to about 94% w/w of the calcium-containingcompound, from about 5 to about 35% w/w of the pharmaceuticallyacceptable sugar alcohol and from about 1 to about 15% w/w of one ormore pharmaceutically acceptable excipients and/or active substances,provided that the sum of ingredients amounts to 100% w/w.
 105. Aparticulate material according to claim 104 containing from about 65% toabout 80% w/w of the calcium-containing compound and from about 15% toabout 25% w/w of sorbitol or isomalt or mixtures thereof.
 106. A soliddosage form comprising a particulate material defined in claim 76 and,optionally, one or more pharmaceutically acceptable excipients oradditives.
 107. A solid dosage form according to claim 106 for oraladministration.
 108. A solid dosage form according to claim 106 in theform of a single unit or a multiple unit dosage form.
 109. A soliddosage form according to claim 108 in the form of tablets, capsules,sachets, beads, pellets or the like.
 110. A solid dosage form accordingto claim 109 in the form of tablets.
 111. A solid dosage form accordingto claim 110, wherein the tablets have a shape and dimensionsessentially as shown in FIG. 24 herein.
 112. A solid dosage formaccording to claims 106 containing an amount of the one or morecalcium-containing compounds corresponding to from about 250 to about1000 mg calcium.
 113. A solid dosage form according to claim 106,wherein the amount of the one or more calcium-containing compoundscorresponds to from about 400 to about 600 mg calcium.
 114. A soliddosage form according to claim 106, wherein the total concentration ofthe one or more calcium-containing compound in the dosage form is in arange of from about 40% to about 99% w/w.
 115. A solid dosage formaccording to claim 106, wherein the total concentration of theparticulate material contained in the dosage form is from about 65% toabout 100% w/w.
 116. A solid dosage form according to claim 106containing from about 60% to about 95% w/w of the calcium-containingcompound and from about 5% to about 40% w/w of the pharmaceuticallyacceptable sugar alcohol, provided that the sum does not exceed 100%w/w.
 117. A solid dosage form according to claim 106 containing fromabout 60 to about 94% w/w of the calcium-containing compound, from about5 to about 35% w/w of the pharmaceutically acceptable sugar alcohol andfrom about 1 to about 15% w/w of one or more pharmaceutically acceptableexcipients and/or active substances, provided that the sum ofingredients amounts to 100% w/w.
 118. A solid dosage form according toclaim 106, wherein a SEM photo of a fractured surface of the soliddosage form shows that a surface of a deformed particle of sugar alcoholis in close contact with surfaces of the crystals of the one or morecalcium-containing compound.
 119. A solid dosage form according to claim106 in the form of tablets, wherein the crushing strength of the tabletswhen stored in open petri dishes at 25° C. and 60% RH at the mostchanges 50% during a time period that starts 5 days after manufactureand runs during the remaining storage period of one month.
 120. A soliddosage form according to claim 106 in the form of a chewable, suckableand/or swallowable tablet.
 121. A solid dosage form according to claim120, which has an acceptable taste with respect to sweetness, flavourand chalkiness when tested by a professional/skilled sensory test panelof at least 6 persons.
 122. A solid dosage form according to claim 106comprising a sweetener selected from the group consisting of dextrose,fructose, glycerin, glucose, isomalt, lactitol, lactose, maltitol,maltose, mannitol, sorbitol, sucrose, tagatose, trehalose, xylitol,alitame, aspartame, acesulfam potassium, cyclamic acid, cyclamate salt,neohesperidine dihydrochalcone, thaumatin, saccharin, saccharin salt(e.g. ammonium saccharin, calcium saccharin, potassium saccharin, sodiumsaccharin), and mixtures thereof.
 123. A process for the preparation ofa particulate material as defined in claim 76, the process comprisingroller compaction of a composition comprising a regularly shapedcalcium-containing compound and one or more pharmaceutically acceptablesugar alcohols having a micro structure.
 124. A process according toclaim 48, wherein the pharmaceutically acceptable sugar alcohol—whencompressed into tablets containing 100% w/w of the sugar alcohol—has aslope of correlation between crushing strength (measured in N) andcompression pressure (measured in N) of 7×10⁻³ or more.
 125. A processaccording to claim 123, wherein the pharmaceutically acceptable sugaralcohol has binding properties.
 126. A process for preparing a tabletcomprising a calcium-containing compound, the process comprises i)preparing a particulate material as defined in claim 76, ii) optionallyadmixing one or more pharmaceutically acceptable excipients or additiveand/or one or more active substances, and iii) compressing the materialinto tablets.
 127. A process according to claim 126, wherein thecompression in step iii) is performed at a compression force that isadjusted with respect to the diameter and the desired height of thetablet so that the compression force applied is at the most about 80 kN.128. A process according to claim 127 for the preparation of a tabletcomprising i) calcium carbonate ii) sorbitol and/or isomalt, iii) avitamin D, and iv) optionally one or more pharmaceutically acceptableexcipients.
 129. A process according to claim 128, wherein the tabletcomprises i) from about 50% to about 90% w/w of calcium carbonate, ii)from about 5 to about 30% w/w of sorbitol and/or isomalt, iii) fromabout 0.01 to about 1% w/w of a vitamin D, and iv) optionally one ormore pharmaceutically acceptable excipients with the proviso that thetotal amount of ingredients corresponds to about 100% w/w.